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Zwart NRK, Kok DE, Ariyaratne SNH, McKay JA. Folate-Associated DNA Methylation and Chemotherapy-Induced Toxicities in Patients With Colorectal Cancer. Mol Nutr Food Res 2025:e70127. [PMID: 40420697 DOI: 10.1002/mnfr.70127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 05/09/2025] [Indexed: 05/28/2025]
Abstract
Patients with stage II-III colorectal cancer (CRC) often receive fluoropyrimidine-based chemotherapy, usually combined with other regimens, of which ∼50% experience severe chemotherapy-induced toxicities. The B-vitamin folate has been associated with toxicity risk, possibly through effects on DNA methylation. Here, we examined the potential role of folate-associated DNA methylation in the context of chemotherapy-induced toxicities. Systematic literature searches were conducted to identify studies investigating either DNA methylation profiles associated with folate status/intake or with toxicities. Overlapping CpG sites and genes across studies investigating associations for "folate-DNA methylation" and "DNA methylation-toxicities" were identified. The probability of overlap was tested using hypergeometric tests and Gene Ontology and KEGG pathway analyses were performed. Six studies were included. A significant number of CpGs and genes overlapped with altered methylation in response to both folate and hand-foot syndrome (HFS) or thrombocytopenia. Moreover, methylation of genes within the KEGG pathway "focal adhesion" was related to folate status/intake and occurrence of HFS, thrombocytopenia, and neutropenia. We identified some overlapping DNA methylation profiles related to both folate exposures and toxicities. This provides preliminary evidence implying folate-associated DNA methylation may determine risk of toxicities, and therefore may be considered a modifiable factor for improving patient outcomes.
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Affiliation(s)
- Nienke R K Zwart
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, The Netherlands
| | - Dieuwertje E Kok
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, The Netherlands
| | | | - Jill A McKay
- Department of Applied Sciences, Northumbria University, Newcastle upon Tyne, UK
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Ho TT, Smith DM, Aquilante CL, Cicali EJ, El Rouby N, Hertz DL, Imanirad I, Patel JN, Scott SA, Swain SM, Tuteja S, Hicks JK, the Pharmacogenomics Global Research Network Publication Committee. A Guide for Implementing DPYD Genotyping for Systemic Fluoropyrimidines into Clinical Practice. Clin Pharmacol Ther 2025; 117:1194-1208. [PMID: 39887719 PMCID: PMC11993294 DOI: 10.1002/cpt.3567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 12/17/2024] [Indexed: 02/01/2025]
Abstract
The safety of systemic fluoropyrimidines (e.g., 5-fluorouracil, capecitabine) is impacted by germline genetic variants in DPYD, which encodes the dihydropyrimidine dehydrogenase (DPD) enzyme that functions as the rate-limiting step in the catabolism of this drug class. Genetic testing to identify those with DPD deficiency can help mitigate the risk of severe and life-threatening fluoropyrimidine-induced toxicities. Globally, the integration of DPYD genetic testing into patient care has varied greatly, ranging from being required as the standard of care in some countries to limited clinical use in others. Thus, implementation strategies have evolved differently across health systems and countries. The primary objective of this tutorial is to provide practical considerations and best practice recommendations for the implementation of DPYD-guided systemic fluoropyrimidine dosing. We adapted the Exploration, Preparation, Implementation, and Sustainment (EPIS) framework to cover topics including the clinical evidence supporting DPYD genotyping to guide fluoropyrimidine therapy, regulatory guidance for DPYD genotyping, key stakeholder engagement, logistics for DPYD genotyping, development of point-of-care clinical decision support tools, and considerations for the creation of sustainable and scalable DPYD genotype-integrated workflows. This guide also describes approaches to counseling patients about DPYD testing and result disclosure, along with examples of patient and provider educational resources. Together, DPYD testing and clinical practice integration aim to promote safe prescribing of fluoropyrimidine therapy and decrease the risk of severe and life-threatening fluoropyrimidine toxicities.
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Affiliation(s)
- Teresa T. Ho
- Department of PathologyH. Lee Moffitt Cancer Center and Research InstituteTampaFloridaUSA
| | - D. Max Smith
- Department of OncologyGeorgetown University Medical CenterWashingtonDistrict of ColumbiaUSA
- MedStar HealthColumbiaMarylandUSA
| | - Christina L. Aquilante
- Department of Pharmaceutical SciencesUniversity of Colorado Skaggs School of Pharmacy and Pharmaceutical SciencesAuroraColoradoUSA
- Colorado Center for Personalized MedicineUniversity of Colorado Anschutz Medical CampusAuroraColoradoUSA
| | - Emily J. Cicali
- Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of PharmacyUniversity of FloridaGainesvilleFloridaUSA
| | - Nihal El Rouby
- Department of Pharmacy Practice and Administrative Sciences, James L Winkle College of PharmacyUniversity of CincinnatiCincinnatiOhioUSA
- St Elizabeth Health CareEdgewoodKentuckyUSA
| | - Daniel L. Hertz
- Department of Clinical PharmacyUniversity of Michigan College of PharmacyAnn ArborMichiganUSA
| | - Iman Imanirad
- Department of Gastrointestinal OncologyH. Lee Moffitt Cancer Center and Research InstituteTampaFloridaUSA
| | - Jai N. Patel
- Division of Cancer Pharmacology & PharmacogenomicsAtrium Health Levine Cancer InstituteCharlotteNorth CarolinaUSA
- Atrium Health Wake Forest Baptist Comprehensive Cancer CenterWinston‐SalemNorth CarolinaUSA
| | - Stuart A. Scott
- Department of PathologyStanford UniversityStanfordCaliforniaUSA
| | - Sandra M. Swain
- MedStar HealthColumbiaMarylandUSA
- Georgetown Lombardi Comprehensive Cancer CenterWashingtonDistrict of ColumbiaUSA
| | - Sony Tuteja
- Division of Translational Medicine and Human Genetics, Department of MedicinePerelman School of MedicinePhiladelphiaPennsylvaniaUSA
| | - J. Kevin Hicks
- Department of PathologyH. Lee Moffitt Cancer Center and Research InstituteTampaFloridaUSA
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Wu J, Dong Y, Zhu W, Meng J, Zhang H, Fang C, Lin L. Capecitabine metronomic chemotherapy for metastatic colorectal cancer patients reaching NED: A protocol for a prospective, randomized, controlled trial. PLoS One 2025; 20:e0320591. [PMID: 40258007 PMCID: PMC12011264 DOI: 10.1371/journal.pone.0320591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 02/19/2025] [Indexed: 04/23/2025] Open
Abstract
INTRODUCTION An increasing number of patients with metastatic colorectal cancer (mCRC) have achieved no evidence of diseases (NED) status after surgery or other treatments. However, the latest guidelines for colorectal cancer do not recommend an appropriate treatment for patients with mCRC who achieve NED status. Capecitabine metronomic chemotherapy has the advantages of significant efficacy and minimal adverse reactions, it is a potential effective method for maintenance treatment for mCRC, but no RCTs have been reported. Therefore, we designed a randomized controlled trial to evaluate the efficacy and safety of capecitabine metronomic chemotherapy for mCRC patients who achieve NED. METHODS/DESIGN This study is a prospective, randomized controlled study that evaluates the efficacy and safety of capecitabine metronomic chemotherapy for patients with mCRC who achieve NED status. 240 eligible participants will be randomly assigned to either a capecitabine metronomic chemotherapy group or a "watch and wait" group at a 1:1 allocation ratio. Eligible patients diagnosed with stage IV mCRC, both the primary tumor and the metastases, are those who have achieved R0 resection (or complete destruction by ablation) and reached NED. Participants who are enrolled in the capecitabine group will receive capecitabine (500 mg/m2 body surface area twice daily) for 2 years. Meanwhile, those who are assigned to the control group will receive regular imaging examination and follow-up only. All participants will follow up for 1 year after receiving 2 years of intervention. The primary outcomes will be disease-free survival (DFS) from randomization, stratified by preoperative chemotherapy, metastatic organs, number of metastases, lenght of previous systemic treatment, response to previous chemotherapy. Secondary outcomes will include overall survival (OS), 1-year,2-year,3-year survival rate and adverse reactions. DISCUSSION As a potentially effective treatment, low-dose capecitabine metronomic chemotherapy has been explored in clinical practice. The results of this trial will provide evidence on the efficacy and safety of capecitabine metronomic chemotherapy for patients with mCRC who have reached NED status. TRIAL REGISTRATION Chinese Clinical Trial Registry (ChiCTR2100047149, protocol version number F2.0).
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Affiliation(s)
- Jiaming Wu
- Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Chinese Medicine, Zhongshan, China
- The First Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yu Dong
- Clinical Research and Big Data Laboratory, South China Research Center for Acupuncture and Moxibustion, Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wanshan Zhu
- Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Chinese Medicine, Zhongshan, China
| | - Jincheng Meng
- Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Chinese Medicine, Zhongshan, China
| | - Huatang Zhang
- Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Chinese Medicine, Zhongshan, China
| | - Cantu Fang
- Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Chinese Medicine, Zhongshan, China
| | - Lizhu Lin
- The First Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
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Randrian V, Dhimene A, Pillet A, Evrard C, Elfadel R, Boyer C, Guyot d'Asnières de Salins A, Ingrand I, Ferru A, Rouleau L, Tougeron D. COVID-19 lockdown-related treatment modifications did not impact the outcome of digestive cancers: the Clin-COVIDICA prospective study. BMC Cancer 2025; 25:398. [PMID: 40045328 PMCID: PMC11881360 DOI: 10.1186/s12885-025-13787-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 02/21/2025] [Indexed: 03/09/2025] Open
Abstract
BACKGROUND The Coronavirus Disease 2019 (COVID-19) pandemic modified the organization of cancer care pathways worldwide. Few prospective long-term data assessing these therapeutic modifications are available. METHODS Clin-COVIDICA was a prospective cohort aiming at determining the clinical impact of COVID-19-related therapeutic modifications in patients with digestive cancer in our center. All consecutive patients undergoing an oncologic treatment for a digestive cancer from March 1 to April 30, 2020, were enrolled in the cohort and followed-up for 24 months. The primary endpoint was progression-free survival (PFS). Secondary endpoints included COVID-19 rate, adverse events (AE) and overall survival (OS). Survival curves were estimated using the Kaplan-Meier method and compared by the log-rank test. RESULTS Of the 401 patients included, 39.6% were female, mean age was 68 years old and most frequent tumor were colorectal (50.0%) and pancreatic (17.9%) cancers. All in all, 55 patients (13.7%) have undergone therapeutic modifications. The most frequent were a switch to an oral drug (capecitabine, 30.9%), treatment holidays (29.1%) and treatment cancellation (18.2%). Considering patients with palliative treatment (n = 339), there was a non-significant trend for longer OS (52.0 months versus 36.4 months, p = 0.07) and a significant longer PFS (15.4 months versus 6.2 months, p = 0.009) in patients with therapeutic modifications. There were more all grades AEs in patients without therapeutic modifications (84.4% vs. 65.5%, p = < 0.001), but more severe AEs (grade 3-5) among patients with therapeutic modifications (18.2% versus 8.7%, p = 0.048), especially for patients with a switch to an oral drug, which resulted in 8 severe adverse events and one death. Six patients (1.5%) had a COVID-19, with one COVID-19-related death and one definitive cancellation of a curative surgery due to the consequences of COVID-19. DISCUSSION We observed no negative survival impact of therapeutic modifications due to the COVID-19 pandemic in digestive cancer management. This may be due to the selection of patients with less aggressive disease. More severe AEs were observed upon therapeutic modifications, especially switching to oral capecitabine. TRIAL REGISTRATION Clinicaltrials.gov: NCT04389684; date of registration (15/05/2020).
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Affiliation(s)
- Violaine Randrian
- Department of Gastroenterology, Poitiers University Hospital, Poitiers, France.
| | - Amale Dhimene
- Department of Gastroenterology, Saintonge Hospital, Saintes, France
| | - Armelle Pillet
- Department of Medical Oncology, Poitiers University Hospital, Poitiers, France
| | - Camille Evrard
- Department of Medical Oncology, Poitiers University Hospital, Poitiers, France
| | - Rayan Elfadel
- Department of Gastroenterology, Belharra Clinic, Bayonne, France
| | - Claire Boyer
- Department of Gastroenterology, Poitiers University Hospital, Poitiers, France
| | | | - Isabelle Ingrand
- Registre des Cancers Poitou-Charentes, Poitiers University, Poitiers, France
| | - Aurélie Ferru
- Department of Medical Oncology, Poitiers University Hospital, Poitiers, France
| | - Laetitia Rouleau
- Department of Gastroenterology, Poitiers University Hospital, Poitiers, France
| | - David Tougeron
- Department of Gastroenterology, Poitiers University Hospital, Poitiers, France
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Arjmandi K, Salahshourifar I, Irani S, Ameli F, Esfandbod M. Association study of TYMS gene expression with TYMS and ENOSF1 genetic variants in neoadjuvant chemotherapy response of gastric cancer. J Pathol Transl Med 2025; 59:105-114. [PMID: 40195828 PMCID: PMC12010872 DOI: 10.4132/jptm.2024.11.05] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 10/29/2024] [Accepted: 11/05/2024] [Indexed: 04/09/2025] Open
Abstract
BACKGROUND The present research was designed to study the associations between genetic variants of TYMS and ENOSF1 genes with TYMS and ENOSF1 gene expression in neoadjuvant chemotherapy response among patients with gastric cancer. METHODS Formalin-embedded and paraffin-fixed matched tumor and normal gastric cancer tissue samples from patients who received neoadjuvant 5-fluorouracil (5-FU) treatment were obtained. DNA and RNA were extracted for all samples. A 28-bp variable number tandem repeat (VNTR) at the 5' untranslated region of TYMS gene and rs2612091 and rs2741171 variants in the ENOSF1 gene were genotyped for normal tissue samples. The real-time polymerase chain reaction method was used to study the expression of ENOSF1 and TYMS genes in both normal and tumor tissues. Data were analyzed using REST 2000 and SPSS ver. 26.0 software programs. RESULTS A significant association between TYMS 2R3R VNTR genotypes and 5-FU therapy was found (p = .032). The 3R3R and 2R2R genotypes were significantly associated with increased and decreased survival time, respectively (p = .003). The 3R3R genotype was significantly associated with TYMS overexpression (p < .001). Moreover, a significant association was found between the rs2612091 genotype and treatment outcome (p = .017). CONCLUSIONS This study highlights the impact of TYMS and ENOSF1 genes as predictive indicators for survival and response to 5-FU-based neoadjuvant chemotherapy in gastric cancer patients.
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Affiliation(s)
- Khadijeh Arjmandi
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Iman Salahshourifar
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Shiva Irani
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Fereshteh Ameli
- Pathology Department, Cancer Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohsen Esfandbod
- Department of Hematology and Oncology, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
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D'Amato M, Iengo G, Massa N, Carlomagno C. Dihydropyrimidine dehydrogenase polymorphisms in patients with gastrointestinal malignancies and their impact on fluoropyrimidine tolerability: Experience from a single Italian institution. World J Gastrointest Oncol 2025; 17:96822. [PMID: 39817118 PMCID: PMC11664602 DOI: 10.4251/wjgo.v17.i1.96822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 08/14/2024] [Accepted: 08/28/2024] [Indexed: 12/12/2024] Open
Abstract
BACKGROUND Fluoropyrimidines are metabolized in the liver by the enzyme dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene. About 7% of the European population is a carrier of DPYD gene polymorphisms associated with reduced DPD enzyme activity. AIM To assess the prevalence of DPYD polymorphisms and their impact on fluoropyrimidine tolerability in Italian patients with gastrointestinal malignancies. METHODS A total of 300 consecutive patients with a diagnosis of gastrointestinal malignancy and treated with a fluoropyrimidine-based regimen were included in the analysis and divided into two cohorts: (1) 149 patients who started fluoropyrimidines after DPYD testing; and (2) 151 patients treated without DPYD testing. Among the patients in cohort A, 15% tested only the DPYD2A polymorphism, 19% tested four polymorphisms (DPYD2A, HapB3, c.2846A>T, and DPYD13), and 66% tested five polymorphisms including DPYD6. RESULTS Overall, 14.8% of patients were found to be carriers of a DPYD variant, the most common being DPYD6 (12.1%). Patients in cohort A reported ≥ G3 toxicities (P = 0.00098), particularly fewer nonhematological toxicities (P = 0.0028) compared with cohort B, whereas there was no statistically significant difference between the two cohorts in hematological toxicities (P = 0.6944). Significantly fewer chemotherapy dose reductions (P = 0.00002) were observed in cohort A compared to cohort B, whereas there was no statistically significant differences in chemotherapy delay. CONCLUSION Although this study had a limited sample size, it provides additional information on the prevalence of DPYD polymorphisms in the Italian population and highlights the role of pharmacogenetic testing to prevent severe toxicity.
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Affiliation(s)
- Mariarosaria D'Amato
- Department of Oncology, Ospedale San Rocco ASL Caserta, Sessa Aurunca 81037, Campania, Italy
| | - Gennaro Iengo
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples 80131, Campania, Italy
| | - Nicola Massa
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples 80131, Campania, Italy
| | - Chiara Carlomagno
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples 80131, Campania, Italy
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Mosch R, van der Lee M, Guchelaar HJ, Swen JJ. Pharmacogenetic Panel Testing: A Review of Current Practice and Potential for Clinical Implementation. Annu Rev Pharmacol Toxicol 2025; 65:91-109. [PMID: 39348848 DOI: 10.1146/annurev-pharmtox-061724-080935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/02/2024]
Abstract
Pharmacogenetics (PGx) aims to optimize drug treatment outcomes by using a patient's genetic profile for individualized drug and dose selection. Currently, reactive and pretherapeutic single-gene PGx tests are increasingly applied in clinical practice in several countries and institutions. With over 95% of the population carrying at least one actionable PGx variant, and with drugs impacted by these genetic variants being in common use, pretherapeutic or preemptive PGx panel testing appears to be an attractive option for better-informed drug prescribing. Here, we discuss the current state of PGx panel testing and explore the potential for clinical implementation. We conclude that available evidence supports the implementation of pretherapeutic PGx panel testing for drugs covered in the PGx guidelines, yet identification of specific patient populations that benefit most and cost-effectiveness data are necessary to support large-scale implementation.
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Affiliation(s)
- R Mosch
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands;
| | - M van der Lee
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands;
| | - H J Guchelaar
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands;
| | - J J Swen
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands;
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Lingyan L, Linjun W, Wenjun Z. Methylenetetrahydrofolate Reductase (MTHFR) Variants and Severe Capecitabine Toxicity: A Case Report and Review of Literature. Cureus 2024; 16:e75791. [PMID: 39816293 PMCID: PMC11734037 DOI: 10.7759/cureus.75791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/15/2024] [Indexed: 01/18/2025] Open
Abstract
Capecitabine is an oral prodrug metabolized into 5-fluorouracil (5-FU) and serves as a representative anticancer agent. While fluoropyrimidine treatment is usually well-tolerated, a subset of patients unfortunately experiences severe and sometimes life-threatening toxicity related to these compounds. This adverse reaction is frequently attributed to partial or complete deficiencies in the dihydropyrimidine dehydrogenase (DPD) enzyme. However, some patients may still suffer from severe toxic effects despite normal DPD screening results when treated with capecitabine. This paper presents the case of a Chinese woman with stage IIIB moderately differentiated adenocarcinoma of the lower rectum (cT3N2aM0) who exhibited severe toxicity after two weeks of neoadjuvant concurrent chemoradiotherapy in TNT mode at a low dose (825mg/m2 bid) of capecitabine. We found that this severe toxicity might be attributable to insufficient methylenetetrahydrofolate reductase (MTHFR) activity. To our knowledge, such reports are scarce in the medical literature concerning the Chinese population.
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Affiliation(s)
- Li Lingyan
- Oncology, Qiannan People's Hospital, Duyun, CHN
| | - Wang Linjun
- Oncology, Qiannan People's Hospital, Duyun, CHN
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Heyvaert M, Denys H, Van Dorpe J, Roels D. Management of severe capecitabine-induced corneal toxicity. Am J Ophthalmol Case Rep 2024; 36:102174. [PMID: 39319200 PMCID: PMC11421284 DOI: 10.1016/j.ajoc.2024.102174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 07/25/2024] [Accepted: 09/12/2024] [Indexed: 09/26/2024] Open
Abstract
Purpose To describe the clinical presentation and management of severe capecitabine-induced corneal toxicity. Observations A 71-year-old woman presented with severe bilateral vision loss. Four months earlier, capecitabine was initiated for a metastatic invasive ductal carcinoma. Biomicroscopy revealed bilateral whorl-like corneal epitheliopathy accompanied by metaplasia, keratinization and subepithelial fibrosis. After consulting the treating oncologist, capecitabine treatment was discontinued. Initially, a non-surgical approach was adopted and intensive topical dexamethasone treatment was applied. Despite capecitabine discontinuation and topical steroid treatment, visual acuity progressively declined. Bilateral corneal scraping and bandage contact lens fitting was performed. This resulted in significant improvement of visual acuity, corneal surface regularity and quality of life. Conclusion and importance We report the first case of severe visual impairment due to capecitabine-induced corneal toxicity. Early corneal scraping, especially when confronted with profound vision loss, may yield better outcomes compared to relying on spontaneous recovery after capecitabine discontinuation. Patients experiencing ocular discomfort and vision loss, while receiving capecitabine therapy, should be referred for semi-urgent ophthalmological examination.
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Affiliation(s)
| | - Hannelore Denys
- Dept of Medical Oncology, Ghent University Hospital, Belgium
- Cancer Research Institute Ghent, Ghent University, Belgium
| | - Jo Van Dorpe
- Dept of Pathology, Ghent University Hospital, Belgium
- Cancer Research Institute Ghent, Ghent University, Belgium
| | - Dimitri Roels
- Dept of Ophthalmology, Ghent University Hospital, Belgium
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10
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Kong D, Wang Z, Wang H, Yang R, Zhang W, Cao L, Nian Y, Ren J, Lu J, Chen T, Duan J, Song Z, Liu T, Hou W, Yoshida S, Shen Z, Bromberg JS, Zheng H. Capecitabine mitigates cardiac allograft rejection via inhibition of TYMS-Mediated Th1 differentiation in mice. Int Immunopharmacol 2024; 141:112955. [PMID: 39163685 DOI: 10.1016/j.intimp.2024.112955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 08/05/2024] [Accepted: 08/13/2024] [Indexed: 08/22/2024]
Abstract
OBJECTIVES Previous studies elucidated that capecitabine (CAP) works as an anti-tumor agent with putative immunosuppressive effects. However, the intricate mechanisms underpinning these effects remain to be elucidated. In this study, we aimed to unravel the molecular pathways by which CAP exerts its immunosuppressive effects to reduce allograft rejection. METHODS Hearts were transplanted from male BALB/c donors to male C57BL/6 recipients and treated with CAP for seven days. The rejection of these heart transplants was assessed using a range of techniques, including H&E staining, immunohistochemistry, RNA sequencing, LS-MS/MS, and flow cytometry. In vitro, naïve CD4+ T cells were isolated and cultured under Th1 condition medium with varying treatments, flow cytometry, LS-MS/MS were employed to delineate the role of thymidine synthase (TYMS) during Th1 differentiation. RESULTS CAP treatment significantly mitigated acute allograft rejection and enhanced graft survival by reducing graft damage, T cell infiltration, and levels of circulating pro-inflammatory cytokines. Additionally, it curtailed CD4+ T cell proliferation and the presence of Th1 cells in the spleen. RNA-seq showed that TYMS, the target of CAP, was robustly increased post-transplantation in splenocytes. In vitro, TYMS and its metabolic product dTMP were differentially expressed in Th0 and Th1, and were required after activation of CD4+ T cell and Th1 differentiation. TYMS-specific inhibitor, raltitrexed, and the metabolite of capecitabine, 5-fluorouracil, could inhibit the proliferation and differentiation of Th1. Finally, the combined use of CAP and the commonly used immunosuppressant rapamycin can induce long-term survival of allograft. CONCLUSION CAP undergoes metabolism conversion to interfere pyrimidine metabolism, which targets TYMS-mediated differentiation of Th1, thereby playing a significant role in mitigating acute cardiac allograft rejection in murine models.
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Affiliation(s)
- Dejun Kong
- Nankai University School of Medicine, Tianjin, China; Department of Organ Transplantation, Tianjin First Central Hospital, Nankai University School of Medicine, Tianjin, China; Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, USA.
| | - Zhenglu Wang
- Department of Organ Transplantation, Tianjin First Central Hospital, Nankai University School of Medicine, Tianjin, China; Tianjin Key Laboratory for Organ Transplantation, Tianjin, China; Institute of Transplantation Medicine, Nankai University, Tianjin, China; Key Laboratory of Transplant Medicine, Chinese Academy of Medical Science, Tianjin, China; Biological Sample Resource Sharing Center, Tianjin First Central Hospital, Nankai University School of Medicine, Tianjin, China.
| | - Hao Wang
- Tianjin Medical University First Central Clinical College, Tianjin, China.
| | - Ruining Yang
- Tianjin Medical University First Central Clinical College, Tianjin, China.
| | - Weiqi Zhang
- Nankai University School of Medicine, Tianjin, China; Department of Organ Transplantation, Tianjin First Central Hospital, Nankai University School of Medicine, Tianjin, China.
| | - Lei Cao
- Biological Sample Resource Sharing Center, Tianjin First Central Hospital, Nankai University School of Medicine, Tianjin, China.
| | - Yeqi Nian
- Department of Organ Transplantation, Tianjin First Central Hospital, Nankai University School of Medicine, Tianjin, China; Institute of Transplantation Medicine, Nankai University, Tianjin, China.
| | - Jiashu Ren
- Tianjin Medical University First Central Clinical College, Tianjin, China.
| | - Jianing Lu
- Tianjin Medical University First Central Clinical College, Tianjin, China.
| | - Tao Chen
- Nankai University School of Medicine, Tianjin, China; Department of Organ Transplantation, Tianjin First Central Hospital, Nankai University School of Medicine, Tianjin, China.
| | - Jinliang Duan
- Nankai University School of Medicine, Tianjin, China; Department of Organ Transplantation, Tianjin First Central Hospital, Nankai University School of Medicine, Tianjin, China.
| | - Zhuolun Song
- Department of Organ Transplantation, Tianjin First Central Hospital, Nankai University School of Medicine, Tianjin, China.
| | - Tao Liu
- National Health Commission's Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin, China.
| | - Wen Hou
- Institute of Transplantation Medicine, Nankai University, Tianjin, China.
| | - Sei Yoshida
- Institute of Transplantation Medicine, Nankai University, Tianjin, China.
| | - Zhongyang Shen
- Nankai University School of Medicine, Tianjin, China; Department of Organ Transplantation, Tianjin First Central Hospital, Nankai University School of Medicine, Tianjin, China; Tianjin Key Laboratory for Organ Transplantation, Tianjin, China; Institute of Transplantation Medicine, Nankai University, Tianjin, China; Key Laboratory of Transplant Medicine, Chinese Academy of Medical Science, Tianjin, China; National Health Commission's Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin, China.
| | - Jonathan S Bromberg
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, USA; Department of Surgery, University of Maryland School of Medicine, Baltimore, USA.
| | - Hong Zheng
- Nankai University School of Medicine, Tianjin, China; Department of Organ Transplantation, Tianjin First Central Hospital, Nankai University School of Medicine, Tianjin, China; Tianjin Key Laboratory for Organ Transplantation, Tianjin, China; Institute of Transplantation Medicine, Nankai University, Tianjin, China; Key Laboratory of Transplant Medicine, Chinese Academy of Medical Science, Tianjin, China; National Health Commission's Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin, China.
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11
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Pratt VM, Cavallari LH, Fulmer ML, Gaedigk A, Hachad H, Ji Y, Kalman LV, Ly RC, Moyer AM, Scott SA, Turner AJ, van Schaik RHN, Whirl-Carrillo M, Weck KE. DPYD Genotyping Recommendations: A Joint Consensus Recommendation of the Association for Molecular Pathology, American College of Medical Genetics and Genomics, Clinical Pharmacogenetics Implementation Consortium, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, European Society for Pharmacogenomics and Personalized Therapy, Pharmacogenomics Knowledgebase, and Pharmacogene Variation Consortium. J Mol Diagn 2024; 26:851-863. [PMID: 39032821 DOI: 10.1016/j.jmoldx.2024.05.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/09/2024] [Accepted: 05/21/2024] [Indexed: 07/23/2024] Open
Abstract
The goals of the Association for Molecular Pathology Clinical Practice Committee's Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This document series provides recommendations for a minimum set of variant alleles (tier 1) and an extended list of variant alleles (tier 2) that will aid clinical laboratories when designing assays for PGx testing. The Association for Molecular Pathology PGx Working Group considered the functional impact of the variant alleles, allele frequencies in multiethnic populations, the availability of reference materials, and other technical considerations for PGx testing when developing these recommendations. The goal of this Working Group is to promote standardization of PGx testing across clinical laboratories. This document will focus on clinical DPYD PGx testing that may be applied to all dihydropyrimidine dehydrogenase-related medications. These recommendations are not to be interpreted as prescriptive but to provide a reference guide.
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Affiliation(s)
- Victoria M Pratt
- Pharmacogenomics Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Agena Bioscience, San Diego, California.
| | - Larisa H Cavallari
- Pharmacogenomics Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, University of Florida, Gainesville, Florida
| | - Makenzie L Fulmer
- Pharmacogenomics Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Pathology and ARUP Laboratories, University of Utah School of Medicine, Salt Lake City, Utah
| | - Andrea Gaedigk
- Pharmacogenomics Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy Research Institute, Kansas City, Missouri; School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri
| | - Houda Hachad
- Pharmacogenomics Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Clinical Operations, AccessDx, Houston, Texas
| | - Yuan Ji
- Pharmacogenomics Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Pathology and ARUP Laboratories, University of Utah School of Medicine, Salt Lake City, Utah
| | - Lisa V Kalman
- Pharmacogenomics Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; Division of Laboratory Systems, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - Reynold C Ly
- Pharmacogenomics Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Ann M Moyer
- Pharmacogenomics Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Stuart A Scott
- Pharmacogenomics Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Pathology, Stanford University, Stanford, California; Clinical Genomics Laboratory, Stanford Medicine, Palo Alto, California
| | - Amy J Turner
- Pharmacogenomics Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Pediatrics, Children's Research Institute, The Medical College of Wisconsin, Milwaukee, Wisconsin; RPRD Diagnostics LLC, Wauwatosa, Wisconsin
| | - Ron H N van Schaik
- Pharmacogenomics Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Clinical Chemistry/International Federation of Clinical Chemistry and Laboratory Medicine Expert Center Pharmacogenetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Michelle Whirl-Carrillo
- Pharmacogenomics Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Biomedical Data Science, Stanford University, Stanford, California
| | - Karen E Weck
- Pharmacogenomics Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina; Department of Genetics, University of North Carolina, Chapel Hill, North Carolina
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12
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Hashimoto Y, Yoshida Y, Yamada T, Yoshimatsu G, Yoshimura F, Hasegawa S. Association Between Changes in Plasma Capecitabine Concentrations and Adverse Events in the Treatment of Colorectal Cancer. Cureus 2024; 16:e71341. [PMID: 39534818 PMCID: PMC11555300 DOI: 10.7759/cureus.71341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/12/2024] [Indexed: 11/16/2024] Open
Abstract
Background Therapeutic drug monitoring (TDM) is an effective approach to improving the efficacy of drugs with a narrow therapeutic index and high toxicity. TDM-guided dosing of 5-fluorouracil (5-FU) has been shown to result in superior efficacy and fewer adverse events compared to body surface area (BSA)-based dosing. Therefore, accurate measurement of plasma 5-FU concentrations after capecitabine administration is necessary. Capecitabine is a prodrug of 5-FU and is metabolized to 5-FU in multiple steps in the gastrointestinal tract, liver, and within tumors. To solve the problem of frequent blood draws for TDM, we reduced the number of blood draws to two and examined whether changes in 5-FU concentration correlated with adverse events. Methods This study investigated the relationship between the changes in plasma 5-FU concentrations after one and two hours of capecitabine administration in 36 patients and adverse events based on drug concentrations determined after adding 5-NU to the plasma samples. Concentration gradients and adverse events were estimated using the Mann-Whitney test. Results The median one- and two-hour plasma 5-FU concentrations were 67.5 (range 5-307) and 85.5 (range 19-246) ng/mL, respectively. The plasma 5-FU concentration gradient, defined as the difference between the one- and two-hour concentrations, was significantly higher in patients with diarrhea and nausea (p = 0.0234 and p = 0.0409, respectively). Conclusion The high plasma 5-FU concentration gradient suggests rapid degradation of 5-FU into its metabolites, which may lead to predict intestinal mucosal damage, diarrhea, and nausea.
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Affiliation(s)
| | - Yoichiro Yoshida
- Gastroenterological Surgery, Fukuoka University Hospital, Fukuoka, JPN
| | - Teppei Yamada
- Gastroenterological Surgery, Fukuoka University Hospital, Fukuoka, JPN
| | - Gumpei Yoshimatsu
- Gastroenterological Surgery, Fukuoka University Hospital, Fukuoka, JPN
| | | | - Suguru Hasegawa
- Gastroenterological Surgery, Fukuoka University Hospital, Fukuoka, JPN
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13
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de Moraes FCA, de Almeida Barbosa AB, Sano VKT, Kelly FA, Burbano RMR. Pharmacogenetics of DPYD and treatment-related mortality on fluoropyrimidine chemotherapy for cancer patients: a meta-analysis and trial sequential analysis. BMC Cancer 2024; 24:1210. [PMID: 39350200 PMCID: PMC11441158 DOI: 10.1186/s12885-024-12981-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 09/23/2024] [Indexed: 10/04/2024] Open
Abstract
BACKGROUND Fluoropyrimidines are chemotherapy drugs utilized to treat a variety of solid tumors. These drugs predominantly rely on the enzyme dihydropyrimidine dehydrogenase (DPD), which is encoded by the DPYD gene, for their metabolism. Genetic mutations affecting this gene can cause DPYD deficiency, disrupting pyrimidine metabolism and increasing the risk of toxicity in cancer patients treated with 5-fluorouracil. The severity and type of toxic reactions are influenced by genetic and demographic factors and, in certain instances, can result in patient mortality. Among the more than 50 identified variants of DPYD, only a subset has clinical significance, leading to the production of enzymes that are either non-functional or impaired. The study aims to examine treatment-related mortality in cancer patients undergoing fluoropyrimidine chemotherapy, comparing those with and without DPD deficiency. METHODS The meta-analysis selected and evaluated 9685 studies from Pubmed, Cochrane, Embase and Web of Science databases. Only studies examining the main DPYD variants (DPYD*2A, DPYD p.D949V, DPYD*13 and DPYD HapB3) were included. Statistical Analysis was performed using R, version 4.2.3. Data were examined using the Mantel-Haenszel method and 95% CIs. Heterogeneity was assessed with I2 statistics. RESULTS There were 36 prospective and retrospective studies included, accounting for 16,005 patients. Most studies assessed colorectal cancer, representing 86.49% of patients. Other gastrointestinal cancers were evaluated by 11 studies, breast cancer by nine studies and head and neck cancers by five studies. Four DPYD variants were identified as predictors of severe fluoropyrimidines toxicity in literature review: DPYD*2A (rs3918290), DPYD p.D949V (rs67376798), DPYD*13 (rs55886062) and DPYD Hap23 (rs56038477). All 36 studies assessed the DPYD*2A variant, while 20 assessed DPYD p.D949V, 7 assessed DPYD*13, and 9 assessed DPYDHap23. Among the 587 patients who tested positive for at least one DPYD variant, 13 died from fluoropyrimidine toxicity. Conversely, in the non-carrier group there were 14 treatment-related deaths. Carriers of DPYD variants was found to be significantly correlated with treatment-related mortality (OR = 34.86, 95% CI 13.96-87.05; p < 0.05). CONCLUSIONS This study improves our comprehension of how the DPYD gene impacts cancer patients receiving fluoropyrimidine chemotherapy. Identifying mutations associated with dihydropyrimidine dehydrogenase deficiency may help predict the likelihood of serious side effects and fatalities. This knowledge can be applied to adjust medication doses before starting treatment, thus reducing the occurrence of these critical outcomes.
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14
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Karatkevich D, Losmanova T, Zens P, Deng H, Dubey C, Zhang T, Casty C, Gao Y, Neppl C, Berezowska S, Wang W, Peng RW, Schmid RA, Dorn P, Marti TM. Chemotherapy increases CDA expression and sensitizes malignant pleural mesothelioma cells to capecitabine treatment. Sci Rep 2024; 14:18206. [PMID: 39107509 PMCID: PMC11303810 DOI: 10.1038/s41598-024-69347-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 08/03/2024] [Indexed: 08/10/2024] Open
Abstract
The combination of cisplatin and pemetrexed remains the gold standard chemotherapy for malignant pleural mesothelioma (MPM), although resistance and poor response pose a significant challenge. Cytidine deaminase (CDA) is a key enzyme in the nucleotide salvage pathway and is involved in the adaptive stress response to chemotherapy. The cytidine analog capecitabine and its metabolite 5'-deoxy-5-fluorocytidine (5'-DFCR) are converted via CDA to 5-fluorouracil, which affects DNA and RNA metabolism. This study investigated a schedule-dependent treatment strategy, proposing that initial chemotherapy induces CDA expression, sensitizing cells to subsequent capecitabine treatment. Basal CDA protein expression was low in different mesothelioma cell lines but increased in the corresponding xenografts. Standard chemotherapy increased CDA protein levels in MPM cells in vitro and in vivo in a schedule-dependent manner. This was associated with epithelial-to-mesenchymal transition and with HIF-1alpha expression at the transcriptional level. In addition, pretreatment with cisplatin and pemetrexed in combination sensitized MPM xenografts to capecitabine. Analysis of a tissue microarray (TMA) consisting of samples from 98 human MPM patients revealed that most human MPM samples had negative CDA expression. While survival curves based on CDA expression in matched samples clearly separated, significance was not reached due to the limited sample size. In non-matched samples, CDA expression before but not after neoadjuvant therapy was significantly associated with worse overall survival. In conclusion, chemotherapy increases CDA expression in xenografts, which is consistent with our in vitro results in MPM and lung cancer. A subset of matched patient samples showed increased CDA expression after therapy, suggesting that a schedule-dependent treatment strategy based on chemotherapy and capecitabine may benefit a selected MPM patient population.
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Affiliation(s)
- Darya Karatkevich
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Murtenstrasse 28, 3008, Bern, Switzerland
- Oncology-Thoracic Malignancies, Department for BioMedical Research, University of Bern, Bern, Switzerland
- Graduate School of Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Tereza Losmanova
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| | - Philipp Zens
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| | - Haibin Deng
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Murtenstrasse 28, 3008, Bern, Switzerland
- Oncology-Thoracic Malignancies, Department for BioMedical Research, University of Bern, Bern, Switzerland
- 2nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
- Hunan Clinical Medical Research Center of Accurate Diagnosis and Treatment for Esophageal Carcinoma, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Christelle Dubey
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Murtenstrasse 28, 3008, Bern, Switzerland
- Oncology-Thoracic Malignancies, Department for BioMedical Research, University of Bern, Bern, Switzerland
| | - Tuo Zhang
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Murtenstrasse 28, 3008, Bern, Switzerland
- Oncology-Thoracic Malignancies, Department for BioMedical Research, University of Bern, Bern, Switzerland
- Graduate School of Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Corsin Casty
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Murtenstrasse 28, 3008, Bern, Switzerland
- Oncology-Thoracic Malignancies, Department for BioMedical Research, University of Bern, Bern, Switzerland
| | - Yanyun Gao
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Murtenstrasse 28, 3008, Bern, Switzerland
- Oncology-Thoracic Malignancies, Department for BioMedical Research, University of Bern, Bern, Switzerland
| | - Christina Neppl
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
- Institute of Pathology, Heinrich-Heine University and University Hospital of Duesseldorf, Duesseldorf, Germany
| | - Sabina Berezowska
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
- Department of Laboratory Medicine and Pathology, Institute of Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Wenxiang Wang
- 2nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
- Hunan Clinical Medical Research Center of Accurate Diagnosis and Treatment for Esophageal Carcinoma, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Ren-Wang Peng
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Murtenstrasse 28, 3008, Bern, Switzerland.
- Oncology-Thoracic Malignancies, Department for BioMedical Research, University of Bern, Bern, Switzerland.
| | - Ralph Alexander Schmid
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Murtenstrasse 28, 3008, Bern, Switzerland.
- Oncology-Thoracic Malignancies, Department for BioMedical Research, University of Bern, Bern, Switzerland.
| | - Patrick Dorn
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Murtenstrasse 28, 3008, Bern, Switzerland.
- Oncology-Thoracic Malignancies, Department for BioMedical Research, University of Bern, Bern, Switzerland.
| | - Thomas Michael Marti
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, University of Bern, Murtenstrasse 28, 3008, Bern, Switzerland.
- Oncology-Thoracic Malignancies, Department for BioMedical Research, University of Bern, Bern, Switzerland.
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15
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Díaz-Villamarín X, Martínez-Pérez M, Nieto-Sánchez MT, Ruiz-Tueros G, Fernández-Varón E, Torres-García A, González Astorga B, Blancas I, Iáñez AJ, Cabeza-Barrera J, Morón R. Novel Genetic Variants Explaining Severe Adverse Drug Events after Clinical Implementation of DPYD Genotype-Guided Therapy with Fluoropyrimidines: An Observational Study. Pharmaceutics 2024; 16:956. [PMID: 39065653 PMCID: PMC11280107 DOI: 10.3390/pharmaceutics16070956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 07/15/2024] [Accepted: 07/16/2024] [Indexed: 07/28/2024] Open
Abstract
Fluoropyrimidines (FPs) are commonly prescribed in many cancer streams. The EMA and FDA-approved drug labels for FPs recommend genotyping the DPYD*2A (rs3918290), *13 (rs55886062), *HapB3 (rs56038477), alleles, and DPYD rs67376798 before treatment starts. We implemented the DPYD genotyping in our daily clinical routine, but we still found patients showing severe adverse drug events (ADEs) to FPs. We studied among these patients the DPYD rs1801265, rs17376848, rs1801159, rs1801160, rs1801158, and rs2297595 as explanatory candidates of the interindividual differences for FP-related toxicities, examining the association with the response to FPs . We also studied the impact of DPYD testing for FP dose tailoring in our clinical practice and characterized the DPYD gene in our population. We found a total acceptance among physicians of therapeutic recommendations translated from the DPYD test, and this dose tailoring does not affect the treatment efficacy. We also found that the DPYD*4 (defined by rs1801158) allele is associated with a higher risk of ADEs (severity grade ≥ 3) in both the univariate (O.R. = 5.66; 95% C.I. = 1.35-23.67; p = 0.014) and multivariate analyses (O.R. = 5.73; 95% C.I. = 1.41-28.77; p = 0.019) among FP-treated patients based on the DPYD genotype. This makes it a candidate variant for implementation in clinical practice.
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Affiliation(s)
- Xando Díaz-Villamarín
- Instituto de Investigación Biosanitaria de Granada (Ibs.Granada), 18012 Granada, Spain
| | | | | | - Gabriela Ruiz-Tueros
- Instituto de Investigación Biosanitaria de Granada (Ibs.Granada), 18012 Granada, Spain
| | - Emilio Fernández-Varón
- Instituto de Investigación Biosanitaria de Granada (Ibs.Granada), 18012 Granada, Spain
- Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18016 Granada, Spain
| | - Alicia Torres-García
- Instituto de Investigación Biosanitaria de Granada (Ibs.Granada), 18012 Granada, Spain
| | - Beatriz González Astorga
- Instituto de Investigación Biosanitaria de Granada (Ibs.Granada), 18012 Granada, Spain
- Medical Oncology, Hospital Universitario San Cecilio, 18016 Granada, Spain
| | - Isabel Blancas
- Instituto de Investigación Biosanitaria de Granada (Ibs.Granada), 18012 Granada, Spain
- Medical Oncology, Hospital Universitario San Cecilio, 18016 Granada, Spain
| | - Antonio J. Iáñez
- Hospital Pharmacy, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain
| | - José Cabeza-Barrera
- Instituto de Investigación Biosanitaria de Granada (Ibs.Granada), 18012 Granada, Spain
- Hospital Pharmacy, Hospital Universitario San Cecilio, 18016 Granada, Spain
| | - Rocío Morón
- Instituto de Investigación Biosanitaria de Granada (Ibs.Granada), 18012 Granada, Spain
- Hospital Pharmacy, Hospital Universitario San Cecilio, 18016 Granada, Spain
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16
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Ziemons J, Hillege LE, Aarnoutse R, de Vos-Geelen J, Valkenburg-van Iersel L, Mastenbroek J, van Geel R, Barnett DJM, Rensen SS, van Helvoort A, Dopheide LHJ, Roeselers G, Penders J, Smidt ML, Venema K. Prebiotic fibre mixtures counteract the manifestation of gut microbial dysbiosis induced by the chemotherapeutic 5-Fluorouracil (5-FU) in a validated in vitro model of the colon. BMC Microbiol 2024; 24:222. [PMID: 38918717 PMCID: PMC11200995 DOI: 10.1186/s12866-024-03384-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 06/18/2024] [Indexed: 06/27/2024] Open
Abstract
BACKGROUND 5-Fluorouracil (5-FU) is used as an antineoplastic agent in distinct cancer types. Increasing evidence suggests that the gut microbiota might modulate 5-FU efficacy and toxicity, potentially affecting the patient's prognosis. The current experimental study investigated 5-FU-induced microbiota alterations, as well as the potential of prebiotic fibre mixtures (M1-M4) to counteract these shifts. METHODS A pooled microbial consortium was derived from ten healthy donors, inoculated in an in vitro model of the colon, and treated with 5-FU, with or without prebiotic fibre mixtures for 72 h. Four different prebiotic fibre mixtures were tested: M1 containing short-chain galacto-oligosaccharides (sc GOS), long-chain fructo-oligosaccharides (lcFOS), and low viscosity pectin (lvPect), M2 consisting of arabinoxylan, beta-glucan, pectin, and resistant starch, M3 which was a mixture of scGOS and lcFOS, and M4 containing arabinoxylan, beta-glucan, pectin, resistant starch, and inulin. RESULTS We identified 5-FU-induced changes in gut microbiota composition, but not in microbial diversity. Administration of prebiotic fibre mixtures during 5-FU influenced gut microbiota composition and taxa abundance. Amongst others, prebiotic fibre mixtures successfully stimulated potentially beneficial bacteria (Bifidobacterium, Lactobacillus, Anaerostipes, Weissella, Olsenella, Senegalimassilia) and suppressed the growth of potentially pathogenic bacteria (Klebsiella, Enterobacter) in the presence of 5-FU. The short-chain fatty acid (SCFA) acetate increased slightly during 5-FU, but even more during 5-FU with prebiotic fibre mixtures, while propionate was lower due to 5-FU with or without prebiotic fibre mixtures, compared to control. The SCFA butyrate and valerate did not show differences among all conditions. The branched-chain fatty acids (BCFA) iso-butyrate and iso-valerate were higher in 5-FU, but lower in 5-FU + prebiotics, compared to control. CONCLUSIONS These data suggest that prebiotic fibre mixtures represent a promising strategy to modulate 5-FU-induced microbial dysbiosis towards a more favourable microbiota, thereby possibly improving 5-FU efficacy and reducing toxicity, which should be evaluated further in clinical studies.
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Affiliation(s)
- Janine Ziemons
- GROW - School for Oncology and Reproduction, Maastricht University, Maastricht, The Netherlands.
- Department of Surgery, Maastricht University Medical Center+, Maastricht, The Netherlands.
| | - Lars E Hillege
- GROW - School for Oncology and Reproduction, Maastricht University, Maastricht, The Netherlands
- Department of Surgery, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Romy Aarnoutse
- GROW - School for Oncology and Reproduction, Maastricht University, Maastricht, The Netherlands
- Department of Surgery, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Judith de Vos-Geelen
- GROW - School for Oncology and Reproduction, Maastricht University, Maastricht, The Netherlands
- Department of Internal Medicine, Division of Medical Oncology, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Liselot Valkenburg-van Iersel
- GROW - School for Oncology and Reproduction, Maastricht University, Maastricht, The Netherlands
- Department of Internal Medicine, Division of Medical Oncology, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Jasper Mastenbroek
- Department of Surgery, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Robin van Geel
- CARIM School for Cardiovascular Disease, Maastricht University, Maastricht, The Netherlands
- Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - David J M Barnett
- Department of Medical Microbiology, Infectious Diseases, and Infection Prevention, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Sander S Rensen
- Department of Surgery, Maastricht University Medical Center+, Maastricht, The Netherlands
- NUTRIM - School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Ardy van Helvoort
- NUTRIM - School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
- Danone Nutricia Research, Utrecht, The Netherlands
| | | | | | - John Penders
- Department of Medical Microbiology, Infectious Diseases, and Infection Prevention, Maastricht University Medical Center+, Maastricht, The Netherlands
- NUTRIM - School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
- Euregional Microbiome Center, Maastricht, The Netherlands
| | - Marjolein L Smidt
- GROW - School for Oncology and Reproduction, Maastricht University, Maastricht, The Netherlands
- Department of Surgery, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Koen Venema
- Euregional Microbiome Center, Maastricht, The Netherlands
- Centre for Healthy Eating & Food Innovation, Maastricht University - Campus Venlo, Venlo, The Netherlands
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17
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Nagy A, Börzsei D, Hoffmann A, Török S, Veszelka M, Almási N, Varga C, Szabó R. A Comprehensive Overview on Chemotherapy-Induced Cardiotoxicity: Insights into the Underlying Inflammatory and Oxidative Mechanisms. Cardiovasc Drugs Ther 2024:10.1007/s10557-024-07574-0. [PMID: 38492161 DOI: 10.1007/s10557-024-07574-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/05/2024] [Indexed: 03/18/2024]
Abstract
While oncotherapy has made rapid progress in recent years, side effects of anti-cancer drugs and treatments have also come to the fore. These side effects include cardiotoxicity, which can cause irreversible cardiac damages with long-term morbidity and mortality. Despite the continuous in-depth research on anti-cancer drugs, an improved knowledge of the underlying mechanisms of cardiotoxicity are necessary for early detection and management of cardiac risk. Although most reviews focus on the cardiotoxic effect of a specific individual chemotherapeutic agent, the aim of our review is to provide comprehensive insight into various agents that induced cardiotoxicity and their underlying mechanisms. Characterization of these mechanisms are underpinned by research on animal models and clinical studies. In order to gain insight into these complex mechanisms, we emphasize the role of inflammatory processes and oxidative stress on chemotherapy-induced cardiac changes. A better understanding and identification of the interplay between chemotherapy and inflammatory/oxidative processes hold some promise to prevent or at least mitigate cardiotoxicity-associated morbidity and mortality among cancer survivors.
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Affiliation(s)
- András Nagy
- Department of Physiology, Anatomy, and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép Fasor 52, 6726, Szeged, Hungary
| | - Denise Börzsei
- Department of Physiology, Anatomy, and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép Fasor 52, 6726, Szeged, Hungary
| | - Alexandra Hoffmann
- Department of Physiology, Anatomy, and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép Fasor 52, 6726, Szeged, Hungary
| | - Szilvia Török
- Department of Physiology, Anatomy, and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép Fasor 52, 6726, Szeged, Hungary
| | - Médea Veszelka
- Department of Physiology, Anatomy, and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép Fasor 52, 6726, Szeged, Hungary
| | - Nikoletta Almási
- Department of Physiology, Anatomy, and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép Fasor 52, 6726, Szeged, Hungary
| | - Csaba Varga
- Department of Physiology, Anatomy, and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép Fasor 52, 6726, Szeged, Hungary
| | - Renáta Szabó
- Department of Physiology, Anatomy, and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép Fasor 52, 6726, Szeged, Hungary.
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Liang Y, Maeda O, Miyata K, Kanda M, Sugita S, Shimizu D, Nishida K, Kodera Y, Ando Y. Genetic polymorphisms as predictive biomarkers of adverse events during preoperative chemotherapy in esophageal cancer. Cancer Chemother Pharmacol 2024; 93:121-127. [PMID: 37898586 DOI: 10.1007/s00280-023-04607-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 10/14/2023] [Indexed: 10/30/2023]
Abstract
PURPOSE This study aimed to explore associations between genetic polymorphisms and adverse effects due to preoperative chemotherapy with docetaxel, cisplatin, and fluorouracil (DCF) for esophageal cancer. METHODS Preoperative DCF (docetaxel, 70 mg/m2/day, day 1; cisplatin, 70 mg/m2/day, day 1; fluorouracil, 750 mg/m2/day, days 1-5) was repeated every 3 weeks for up to three cycles. Genotyping of nine candidate genetic polymorphisms was conducted using blood samples from the enrolled patients. RESULTS According to a multivariable analysis evaluating 50 patients, grade 3 or worse neutropenia was more likely to occur in those with the ABCC2-24C/T or T/T genotype (rs717620) (OR, 5.30, P = 0.013). Additionally, patients with the TYMS 3'-UTR 0 bp/0 bp genotype (rs151264360) showed a trend toward grade 3 or worse hyponatremia (OR, 0.16, P = 0.005). Grade 2 or worse thrombocytopenia was more likely to occur in patients with the TNF-α-1031C/T or T/T genotype (rs1799964) (OR, 6.30, P = 0.016) and IL-6-634C/C genotype (rs1800796) (OR, 0.18, P = 0.034), and grade 2 or worse anemia was more likely to occur in patients with the MCP-1-2518G/G genotype (rs1024611) (OR, 0.19, P = 0.027). CONCLUSIONS ABCC2-24C > T (rs717620), TYMS 3'-UTR 6-bp indel (rs151264360), TNF-α-1031T > C (rs1799964) as well as IL-6-634G > C (rs1800796), and MCP-1-2518A > G (rs1024611) polymorphisms might serve as independent and predictive biomarkers for neutropenia, hyponatremia, thrombocytopenia, and anemia, respectively, during preoperative chemotherapy with docetaxel, cisplatin, and fluorouracil for patients with esophageal cancer.
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Affiliation(s)
- Yao Liang
- Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan
| | - Osamu Maeda
- Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan.
| | - Kazushi Miyata
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shizuki Sugita
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Dai Shimizu
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kazuki Nishida
- Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuichi Ando
- Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan
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19
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Zhou DB, Cheng J, Zhang XH. Evaluating combined bevacizumab and XELOX in advanced colorectal cancer: Serum markers carcinoembryonic antigen, carbohydrate antigen 125, carbohydrate antigen 199 analysis. World J Clin Cases 2024; 12:15-23. [PMID: 38292648 PMCID: PMC10824169 DOI: 10.12998/wjcc.v12.i1.15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 11/23/2023] [Accepted: 12/18/2023] [Indexed: 01/02/2024] Open
Abstract
BACKGROUND Colorectal cancer ranks third and second among common and fatal cancers. The treatment of metastatic colorectal cancer (mCRC) is generally based on XELOX in clinical practice, which includes capecitabine (CAP) and oxaliplatin. Serum tumor markers carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 125 and CA199 are prognostic factors for various tumors. AIM To investigate evaluating combined bevacizumab (BEV) and XELOX in advanced colorectal cancer: Serum markers CEA, CA125, CA199 analysis. METHODS In this retrospective study, a total of 94 elderly patients diagnosed with mCRC were recruited and subsequently categorized into two groups based on the distinct treatment modalities they received. The control group was treated with XELOX plus CAP (n = 47), while the observation group was treated with XELOX plus CAP and BEV (n = 47). Several indexes were assessed in both groups, including disease control rate (DCR), incidence of adverse effects, serum marker levels (CEA, CA125, and CA19) and progression-free survival (PFS). RESULTS After 9 wk of treatment, the serum levels of CEA, CA199 and CA125 in the observation group were significantly lower than those in the control group (P < 0.05). Moreover, the PFS of the observation group (9.12 ± 0.90 mo) was significantly longer than that of the control group (6.49 ± 0.64 mo). Meanwhile, there was no statistically significant difference in the incidence of adverse reactions and DCR between the two groups during maintenance therapy (P > 0.05). CONCLUSION On the basis of XELOX treatment, the combination of BEV and CAP can reduce serum tumor marker levels and prolong PFS in patients with mCRC.
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Affiliation(s)
- Dong-Bing Zhou
- Department of Gastroenterology, The Second People's Hospital of Jingzhou Hubei, Jingzhou 434000, Hubei Province, China
| | - Jun Cheng
- Department of Gastrointestinal Surgery, Qianjiang Central Hospital, Qianjing 433100, Hubei Province, China
| | - Xiong-Hui Zhang
- Department of Gastroenterology, Xiantao First People's Hosepital Affiliated to Yangtze University, Xiantao 433000, Hubei Province, China
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20
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Boye A, Asiamah EA, Martey O, Ayertey F. Citrus limon (L.) Osbeck Fruit Peel Extract Attenuates Carbon Tetrachloride-Induced Hepatocarcinogenesis in Sprague-Dawley Rats. BIOMED RESEARCH INTERNATIONAL 2024; 2024:6673550. [PMID: 38204757 PMCID: PMC10776197 DOI: 10.1155/2024/6673550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 12/16/2023] [Accepted: 12/19/2023] [Indexed: 01/12/2024]
Abstract
Background Traditional herbal medicine practitioners in the Ashanti region of Ghana use the fruit peels of Citrus limon (L.) Osbeck (C. limon) in preventive and curative treatment of many cancers including liver cancer. This ethnobotanical claim remains to be verified scientifically. Aim of the Study. This study investigated prophylactic hepatoprotective and anti-HCC effects of C. limon peel extract (LPE) in CCl4/olive oil-induced HCC-like rats. Materials and Methods After preparation of LPE, it was subjected to phytochemical screening using standard phytochemical methods. A total of 30 healthy adult male Sprague-Dawley rats (weighing 150-200 g) were randomly assigned into six groups of 5 rats each. Rats in the control group received olive oil (5 mL/kg ip) twice weekly for 16 weeks. Rats in the model group received CCl4/olive oil (2 mL/kg, ip) twice weekly for 16 weeks. Rats in capecitabine (10 mg/kg po) and LPE (50, 100, and 200 mg/kg po) groups received CCl4/olive oil (2 mL/kg, i.p) in the morning and their respective treatments in the afternoon twice a week for 16 weeks. Rats in all groups had free access to food and water ad libitum. Body weight and survival rates were monitored. Rats were sacrificed under deep anesthesia, blood was collected, and liver and other organs were isolated. Aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), prothrombin time, bilirubin, C-reactive protein (CRP), alpha- (α-) fetoprotein (AFP), and liver histology were assessed. Results Alkaloids, tannins, flavonoids, terpenoids, and saponins were detected in LPE. Model rats demonstrated increased serum levels of AFP, CRP, ALP, GGT, ALT, and AST, prothrombin time, total bilirubin, direct bilirubin, blood lymphocyte, and monocyte counts, but decreased serum albumin and total protein compared to control rats. Unlike the control, model rats demonstrated fat accumulation in periportal and centrilobular hepatocytes and neoplastic transformation. Semiquantitation of periodic acid Schiff- (PAS-) stained liver sections showed decreased glycogen storage in hepatocytes of model rats compared to control rats. Compared to the model, LPE treatment protected against CCl4-induced hepatocarcinogenesis, which was evidenced by decreased AFP, CRP, liver enzymes, total and direct bilirubin, prothrombin time, and blood lymphocyte and monocyte counts; attenuation of fat accumulation; and increased glycogen storage, albumin, and total protein. Conclusion LPE abates CCl4-induced hepatocarcinogenesis by attenuating liver inflammation and improving metabolic, biosynthetic, and detoxification functions of the liver. The prophylactic hepatoprotective and anti-hepatocarcinogenic effects of LPE are attributable to its phytochemical composition raising hopes of finding potential anticancer bioactive compounds from C. limon fruit peels.
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Affiliation(s)
- Alex Boye
- Department of Medical Laboratory Science, School of Allied Health Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Ernest Amponsah Asiamah
- Department of Biomedical Science, School of Allied Health Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Orleans Martey
- Department of Pharmacology, Center for Plant Medicine Research, Mampong-Akuapem, Eastern Region, Ghana
| | - Frederick Ayertey
- Department of Phytochemistry, Center for Plant Medicine Research, Mampong-Akuapem, Eastern Region, Ghana
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21
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Tavakoli Pirzaman A, Mansoori R, Hosseini SM, Abolhosseini A, Khosravi S, Moghadamnia AA, Kazemi S. The effect of melatonin on capecitabine-induced hepatic and renal toxicity in rats. Hum Exp Toxicol 2024; 43:9603271231223506. [PMID: 38179616 DOI: 10.1177/09603271231223506] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2024]
Abstract
BACKGROUND Capecitabine (CAPE), an antimetabolite chemotherapy, can induce hepatic and renal toxicity. Melatonin (MEL), a neurohormone, possesses antioxidant, anti-apoptotic and anti-inflammatory effects. This study investigated the impact of MEL on capecitabine-induced hepatic and renal toxicity. METHODS AND MATERIALS Twenty-five male Wistar rats were categorized into five groups for the study. The groups included a control group, MEL10 group (rats receiving daily intraperitoneal injections of 5 mg/kg MEL), CAPE 500 group (rats receiving weekly intraperitoneal injections of 500 mg/kg CAPE), CAPE + MEL five group, and CAPE + MEL 10 group. All groups were treated for a duration of 6 weeks. Various hematological, serological, biochemical, and histopathological assessments were conducted to evaluate the objective of the study. RESULTS The administration of CAPE led to significant liver and kidney toxicity, as evidenced by elevated levels of malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NO), as well as serological markers including AST, ALT, ALP, BUN, and creatinine. CAPE exposure also resulted in a reduction in total antioxidant capacity (TAC) and glutathione peroxidase (GPx) levels. Histological examination revealed hyperemia in both liver and kidney tissues exposed to CAPE. However, treatment with MEL demonstrated positive effects. MEL administration alleviated oxidative stress, reduced levels of liver enzymes, BUN, and creatinine, and ameliorated histopathological degenerations. MEL also increased GPx and TAC levels. Moreover, MEL treatment aided in restoring the body weight that was lost due to CAPE exposure. CONCLUSION Our findings indicated that the administration of MEL in rats significantly enhanced the hepatic and renal toxicity induced by CAPE.
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Affiliation(s)
| | - Razieh Mansoori
- Department of Pharmacology and Toxicology, School of Medicine, Babol University of Medical Science, Babol, Iran
| | | | - Ali Abolhosseini
- Student Research Committee, Babol University of Medical Science, Babol, Iran
| | - Sahar Khosravi
- Cancer Research Center, Health Research Institute, Babol University of Medical Science, Babol, Iran
| | - Ali Akbar Moghadamnia
- Pharmaceutical Sciences Research Center, Health Research Institute, Babol University of Medical Science, Babol, Iran
| | - Sohrab Kazemi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Science, Babol, Iran
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Chaurasia M, Singh R, Sur S, Flora SJS. A review of FDA approved drugs and their formulations for the treatment of breast cancer. Front Pharmacol 2023; 14:1184472. [PMID: 37576816 PMCID: PMC10416257 DOI: 10.3389/fphar.2023.1184472] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 06/23/2023] [Indexed: 08/15/2023] Open
Abstract
Breast cancer is one of the most diagnosed solid cancers globally. Extensive research has been going on for decades to meet the challenges of treating solid tumors with selective compounds. This article aims to summarize the therapeutic agents which are either being used or are currently under approval for use in the treatment or mitigation of breast cancer by the US FDA, to date. A structured search of bibliographic databases for previously published peer-reviewed research papers on registered molecules was explored and data was sorted in terms of various categories of drugs used in first line/adjuvant therapy for different stages of breast cancer. We included more than 300 peer-reviewed papers, including both research and reviews articles, in order to provide readers an useful comprehensive information. A list of 39 drugs are discussed along with their current status, dose protocols, mechanism of action, pharmacokinetics, possible side effects, and marketed formulations. Another interesting aspect of the article included focusing on novel formulations of these drugs which are currently in clinical trials or in the process of approval. This exhaustive review thus shall be a one-stop solution for researchers who are working in the areas of formulation development for these drugs.
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Affiliation(s)
| | | | | | - S. J. S. Flora
- Era College of Pharmacy, Era University, Lucknow, Uttar Pradesh, India
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23
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Chi L, Wang H, Yu F, Gao C, Dai H, Si X, Dong Y, Liu H, Zhang Q. Design, synthesis and biological evaluation of nitric oxide-releasing 5-cyano-6-phenyl-2, 4-disubstituted pyrimidine derivatives. Bioorg Med Chem Lett 2023:129389. [PMID: 37379957 DOI: 10.1016/j.bmcl.2023.129389] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 06/09/2023] [Accepted: 06/22/2023] [Indexed: 06/30/2023]
Abstract
In this study, a series of nitric oxide (NO) -releasing 5-cyano-6-phenyl-2, 4-disubstituted pyrimidine derivatives were designed and synthesized. In the in vitro biological evaluation, compound 24l exhibited optimal antiproliferative activity against MGC-803 cells with the IC50 value of 0.95 µM, significantly better than that of the positive control 5-FU. In addition, preliminary mechanistic studies indicated that 24l inhibited colony formation and blocked MGC-803 cells in the G0/G1 phase. DAPI staining, reactive oxygen species and apoptosis assays demonstrated that 24l induced apoptosis of MGC-803 cells. Particularly, the most potent compound 24l produced the highest level of NO, and the antiproliferative activity was significantly reduced after preincubation with NO scavengers. In conclusion, compound 24l may be considered as a potential candidate antitumor agent.
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Affiliation(s)
- Lingling Chi
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Institute of Drug Discovery and Development, Zhengzhou 450001, China
| | - Hao Wang
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Institute of Drug Discovery and Development, Zhengzhou 450001, China
| | - Fuqiang Yu
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Institute of Drug Discovery and Development, Zhengzhou 450001, China
| | - Chao Gao
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Institute of Drug Discovery and Development, Zhengzhou 450001, China
| | - Honglin Dai
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Institute of Drug Discovery and Development, Zhengzhou 450001, China
| | - Xiaojie Si
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Institute of Drug Discovery and Development, Zhengzhou 450001, China
| | - Yuze Dong
- Institute of Drug Discovery and Development, Zhengzhou 450001, China; Center for Drug Safety Evaluation and Research, Zhengzhou 450001, China
| | - Hongmin Liu
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Institute of Drug Discovery and Development, Zhengzhou 450001, China; Center for Drug Safety Evaluation and Research, Zhengzhou 450001, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou 450052, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou 450001, China
| | - Qiurong Zhang
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Institute of Drug Discovery and Development, Zhengzhou 450001, China; Center for Drug Safety Evaluation and Research, Zhengzhou 450001, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou 450052, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou 450001, China
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Gu L, Hickey RJ, Malkas LH. Therapeutic Targeting of DNA Replication Stress in Cancer. Genes (Basel) 2023; 14:1346. [PMID: 37510250 PMCID: PMC10378776 DOI: 10.3390/genes14071346] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 06/06/2023] [Accepted: 06/07/2023] [Indexed: 07/30/2023] Open
Abstract
This article reviews the currently used therapeutic strategies to target DNA replication stress for cancer treatment in the clinic, highlighting their effectiveness and limitations due to toxicity and drug resistance. Cancer cells experience enhanced spontaneous DNA damage due to compromised DNA replication machinery, elevated levels of reactive oxygen species, loss of tumor suppressor genes, and/or constitutive activation of oncogenes. Consequently, these cells are addicted to DNA damage response signaling pathways and repair machinery to maintain genome stability and support survival and proliferation. Chemotherapeutic drugs exploit this genetic instability by inducing additional DNA damage to overwhelm the repair system in cancer cells. However, the clinical use of DNA-damaging agents is limited by their toxicity and drug resistance often arises. To address these issues, the article discusses a potential strategy to target the cancer-associated isoform of proliferating cell nuclear antigen (caPCNA), which plays a central role in the DNA replication and damage response network. Small molecule and peptide agents that specifically target caPCNA can selectively target cancer cells without significant toxicity to normal cells or experimental animals.
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Affiliation(s)
- Long Gu
- Department of Molecular Diagnostics & Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Robert J Hickey
- Department of Cancer Biology & Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Linda H Malkas
- Department of Molecular Diagnostics & Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
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25
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Wang H, Wang ZL, Zhang S, Kong DJ, Yang RN, Cao L, Wang JX, Yoshida S, Song ZL, Liu T, Fan SL, Ren JS, Li JH, Shen ZY, Zheng H. Metronomic capecitabine inhibits liver transplant rejection in rats by triggering recipients' T cell ferroptosis. World J Gastroenterol 2023; 29:3084-3102. [PMID: 37346150 PMCID: PMC10280797 DOI: 10.3748/wjg.v29.i20.3084] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Revised: 02/19/2023] [Accepted: 04/28/2023] [Indexed: 05/26/2023] Open
Abstract
BACKGROUND Capecitabine (CAP) is a classic antimetabolic drug and has shown potential antirejection effects after liver transplantation (LT) in clinical studies. Our previous study showed that metronomic CAP can cause the programmed death of T cells by inducing oxidative stress in healthy mice. Ferroptosis, a newly defined non-apoptotic cell death that occurs in response to iron overload and lethal levels of lipid peroxidation, is an important mechanism by which CAP induces cell death. Therefore, ferroptosis may also play an important role in CAP-induced T cell death and play an immunosuppressive role in acute rejection after trans-plantation. AIM To investigate the functions and underlying mechanisms of antirejection effects of metronomic CAP. METHODS A rat LT model of acute rejection was established, and the effect of metronomic CAP on splenic hematopoietic function and acute graft rejection was evaluated 7 d after LT. In vitro, primary CD3+ T cells were sorted from rat spleens and human peripheral blood, and co-cultured with or without 5-fluorouracil (5-FU) (active agent of CAP). The levels of ferroptosis-related proteins, ferrous ion concentration, and oxidative stress-related indicators were observed. The changes in mito-chondrial structure were observed using electron microscopy. RESULTS With no significant myelotoxicity, metronomic CAP alleviated graft injury (Banff score 9 vs 7.333, P < 0.001), prolonged the survival time of the recipient rats (11.5 d vs 16 d, P < 0.01), and reduced the infiltration rate of CD3+ T cells in peripheral blood (6.859 vs 3.735, P < 0.001), liver graft (7.459 vs 3.432, P < 0.001), and spleen (26.92 vs 12.9, P < 0.001), thereby inhibiting acute rejection after LT. In vitro, 5-FU, an end product of CAP metabolism, induced the degradation of the ferritin heavy chain by upregulating nuclear receptor coactivator 4, which caused the accumulation of ferrous ions. It also inhibited nuclear erythroid 2 p45-related factor 2, heme oxygenase-1, and glutathione peroxidase 4, eventually leading to oxidative damage and ferroptosis of T cells. CONCLUSION Metronomic CAP can suppress acute allograft rejection in rats by triggering CD3+ T cell ferroptosis, which makes it an effective immunosuppressive agent after LT.
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Affiliation(s)
- Hao Wang
- The First Central Clinical School, Tianjin Medical University, Tianjin 300190, China
| | - Zheng-Lu Wang
- Department of Organ Transplant, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300190, China
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300190, China
| | - Sai Zhang
- School of Medicine, Nankai University, Tianjin 300190, China
| | - De-Jun Kong
- School of Medicine, Nankai University, Tianjin 300190, China
| | - Rui-Ning Yang
- The First Central Clinical School, Tianjin Medical University, Tianjin 300190, China
| | - Lei Cao
- Research Institute of Transplant Medicine, Nankai University, Tianjin 300071, China
- Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300071, China
| | - Jian-Xi Wang
- Research Institute of Transplant Medicine, Nankai University, Tianjin 300071, China
- Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300071, China
| | - Sei Yoshida
- Research Institute of Transplant Medicine, Nankai University, Tianjin 300071, China
| | - Zhuo-Lun Song
- Department of Organ Transplant, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300190, China
| | - Tao Liu
- National Health Commission’s Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300071, China
| | - Shun-Li Fan
- Department of Organ Transplant, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300190, China
| | - Jia-Shu Ren
- The First Central Clinical School, Tianjin Medical University, Tianjin 300190, China
| | - Jiang-Hong Li
- The First Central Clinical School, Tianjin Medical University, Tianjin 300190, China
| | - Zhong-Yang Shen
- Department of Organ Transplant, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300190, China
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300190, China
- Research Institute of Transplant Medicine, Nankai University, Tianjin 300071, China
- Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300071, China
- National Health Commission’s Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300071, China
| | - Hong Zheng
- Department of Organ Transplant, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300190, China
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300190, China
- Research Institute of Transplant Medicine, Nankai University, Tianjin 300071, China
- Tianjin Key Laboratory for Organ Transplantation, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin 300071, China
- National Health Commission’s Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin 300071, China
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26
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Baker SD, Bates SE, Brooks GA, Dahut WL, Diasio RB, El-Deiry WS, Evans WE, Figg WD, Hertz DL, Hicks JK, Kamath S, Kasi PM, Knepper TC, McLeod HL, O'Donnell PH, Relling MV, Rudek MA, Sissung TM, Smith DM, Sparreboom A, Swain SM, Walko CM. DPYD Testing: Time to Put Patient Safety First. J Clin Oncol 2023; 41:2701-2705. [PMID: 36821823 PMCID: PMC10414691 DOI: 10.1200/jco.22.02364] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 12/02/2022] [Accepted: 01/17/2023] [Indexed: 02/25/2023] Open
Affiliation(s)
- Sharyn D. Baker
- College of Pharmacy, The Ohio State University, Columbus, OH
| | - Susan E. Bates
- Herbert Irving Comprehensive Cancer Center, Columbia University, Irving Medical Center, New York, NY
| | | | | | | | | | | | - William D. Figg
- Clinical Pharmacology Program, National Cancer Institute, Bethesda, MD
| | - Dan L. Hertz
- College of Pharmacy, University of Michigan, Ann Arbor, MI
| | - J. Kevin Hicks
- Department of Individualized Cancer Management, Moffitt Cancer Center, Tampa, FL
| | - Suneel Kamath
- Cleveland Clinic, Lerner College of Medicine, Cleveland, OH
| | | | - Todd C. Knepper
- Department of Individualized Cancer Management, Moffitt Cancer Center, Tampa, FL
| | | | | | | | | | | | - D. Max Smith
- Georgetown Lombardi Comprehensive Cancer Center and MedStar Health, Georgetown University, Washington, DC
| | - Alex Sparreboom
- College of Pharmacy, The Ohio State University, Columbus, OH
| | - Sandra M. Swain
- Georgetown Lombardi Comprehensive Cancer Center and MedStar Health, Georgetown University, Washington, DC
| | - Christine M. Walko
- Department of Individualized Cancer Management, Moffitt Cancer Center, Tampa, FL
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Maslarinou A, Manolopoulos VG, Ragia G. Pharmacogenomic-guided dosing of fluoropyrimidines beyond DPYD: time for a polygenic algorithm? Front Pharmacol 2023; 14:1184523. [PMID: 37256234 PMCID: PMC10226670 DOI: 10.3389/fphar.2023.1184523] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 04/19/2023] [Indexed: 06/01/2023] Open
Abstract
Fluoropyrimidines are chemotherapeutic agents widely used for the treatment of various solid tumors. Commonly prescribed FPs include 5-fluorouracil (5-FU) and its oral prodrugs capecitabine (CAP) and tegafur. Bioconversion of 5-FU prodrugs to 5-FU and subsequent metabolic activation of 5-FU are required for the formation of fluorodeoxyuridine triphosphate (FdUTP) and fluorouridine triphosphate, the active nucleotides through which 5-FU exerts its antimetabolite actions. A significant proportion of FP-treated patients develop severe or life-threatening, even fatal, toxicity. It is well known that FP-induced toxicity is governed by genetic factors, with dihydropyrimidine dehydrogenase (DPYD), the rate limiting enzyme in 5-FU catabolism, being currently the cornerstone of FP pharmacogenomics. DPYD-based dosing guidelines exist to guide FP chemotherapy suggesting significant dose reductions in DPYD defective patients. Accumulated evidence shows that additional variations in other genes implicated in FP pharmacokinetics and pharmacodynamics increase risk for FP toxicity, therefore taking into account more gene variations in FP dosing guidelines holds promise to improve FP pharmacotherapy. In this review we describe the current knowledge on pharmacogenomics of FP-related genes, beyond DPYD, focusing on FP toxicity risk and genetic effects on FP dose reductions. We propose that in the future, FP dosing guidelines may be expanded to include a broader ethnicity-based genetic panel as well as gene*gene and gender*gene interactions towards safer FP prescription.
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Affiliation(s)
- Anthi Maslarinou
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
- Individualised Medicine and Pharmacological Research Solutions Center, Alexandroupolis, Greece
| | - Vangelis G. Manolopoulos
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
- Individualised Medicine and Pharmacological Research Solutions Center, Alexandroupolis, Greece
- Clinical Pharmacology Unit, Academic General Hospital of Alexandroupolis, Alexandroupolis, Greece
| | - Georgia Ragia
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
- Individualised Medicine and Pharmacological Research Solutions Center, Alexandroupolis, Greece
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Guijarro MV, Kellish PC, Dib PE, Paciaroni NG, Nawab A, Andring J, Kulemina L, Borrero NV, Modenutti C, Feely M, Nasri E, Seifert RP, Luo X, Bennett RL, Shabashvili D, Licht JD, McKenna R, Roitberg A, Huigens RW, Kaye FJ, Zajac-Kaye M. First-in-class multifunctional TYMS nonclassical antifolate inhibitor with potent in vivo activity that prolongs survival. JCI Insight 2023; 8:e158798. [PMID: 37097751 PMCID: PMC10386886 DOI: 10.1172/jci.insight.158798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 04/18/2023] [Indexed: 04/26/2023] Open
Abstract
Although thymidylate synthase (TYMS) inhibitors have served as components of chemotherapy regimens, the currently available inhibitors induce TYMS overexpression or alter folate transport/metabolism feedback pathways that tumor cells exploit for drug resistance, limiting overall benefit. Here we report a small molecule TYMS inhibitor that i) exhibited enhanced antitumor activity as compared with current fluoropyrimidines and antifolates without inducing TYMS overexpression, ii) is structurally distinct from classical antifolates, iii) extended survival in both pancreatic xenograft tumor models and an hTS/Ink4a/Arf null genetically engineered mouse tumor model, and iv) is well tolerated with equal efficacy using either intraperitoneal or oral administration. Mechanistically, we verify the compound is a multifunctional nonclassical antifolate, and using a series of analogs, we identify structural features allowing direct TYMS inhibition while maintaining the ability to inhibit dihydrofolate reductase. Collectively, this work identifies nonclassical antifolate inhibitors that optimize inhibition of thymidylate biosynthesis with a favorable safety profile, highlighting the potential for enhanced cancer therapy.
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Affiliation(s)
| | | | | | | | | | - Jacob Andring
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA
| | | | | | - Carlos Modenutti
- Department of Biological Chemistry, Faculty of Exact and Natural Sciences, University of Buenos Aires, and
- Institute of Biological Chemistry of the Faculty of Exact and Natural Sciences (IQUIBICEN) CONICET, University City, Pab. II (CE1428EHA), Buenos Aires, Argentina
| | - Michael Feely
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Elham Nasri
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Robert P. Seifert
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, USA
| | | | - Richard L. Bennett
- Department of Medicine, University of Florida Health Cancer Center, Gainesville, Florida, USA
| | | | - Jonathan D. Licht
- Department of Medicine, University of Florida Health Cancer Center, Gainesville, Florida, USA
| | - Robert McKenna
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA
| | - Adrian Roitberg
- Department of Chemistry, University of Florida, Gainesville, Florida, USA
| | | | - Frederic J. Kaye
- Department of Medicine, University of Florida Health Cancer Center, Gainesville, Florida, USA
| | - Maria Zajac-Kaye
- Department of Anatomy and Cell Biology
- Department of Medicine, University of Florida Health Cancer Center, Gainesville, Florida, USA
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Seltzer JA, Friedman NA, Hardin J, Galust H, Cantrell FL, Minns A. Oral Capecitabine Exposures and Use of Uridine Triacetate: A 20-Year Retrospective Analysis. Clin Drug Investig 2023; 43:359-363. [PMID: 37072662 DOI: 10.1007/s40261-023-01268-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/05/2023] [Indexed: 04/20/2023]
Abstract
BACKGROUND AND OBJECTIVES Capecitabine is an oral prodrug of 5-fluorouracil. Toxicity can occur during therapy as well as acutely with overdose and particular genetic susceptibilities. Uridine triacetate is an effective antidote if given within 96 h of exposure. This study seeks to characterize accidental and intentional capecitabine exposures and uridine triacetate use, about which little has been published. METHODS A retrospective review of capecitabine exposures from 30 April 2001 to 31 December 2021 reported to a statewide poison control center was performed. All single-substance oral exposures were included. RESULTS In total, 81 of 128 reviewed cases were included, with a median age of 63 years. In total, 49 were acute-on-chronic exposures and 32 were acute exposures in capecitabine-naïve patients, 29 of which were accidental. Fifty-six (69%) were managed at home. Of these, none later recontacted the poison control center to report symptoms or were known to have later had healthcare facility evaluations. Of the 25 cases presenting for healthcare facility evaluation, 4 were acutely symptomatic. Thirteen were eligible for uridine triacetate, and six received it; no new or progressive toxicity was reported after. Three developed mild latent toxicity; otherwise, no morbidity or mortality was reported. CONCLUSIONS Accidental acute-on-chronic and acute ingestions of capecitabine appear to be well tolerated; most cases were managed at home. Unfortunately, little is known regarding the threshold at which toxicity may present following exposures. The threshold may vary individually given genetic susceptibilities. Management was heterogeneous, likely reflecting inadequate guidelines. Further research is needed to better delineate at-risk populations and treatment strategies.
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Affiliation(s)
- Justin A Seltzer
- Division of Medical Toxicology, Department of Emergency Medicine, UC San Diego Health, 200 W. Arbor Dr. #8676, San Diego, CA, 92103, USA.
- California Poison Control System, San Diego, CA, USA.
- VA San Diego Healthcare System, San Diego, CA, USA.
| | - Nathan A Friedman
- Division of Medical Toxicology, Department of Emergency Medicine, UC San Diego Health, 200 W. Arbor Dr. #8676, San Diego, CA, 92103, USA
- California Poison Control System, San Diego, CA, USA
- VA San Diego Healthcare System, San Diego, CA, USA
| | - Jeremy Hardin
- Division of Medical Toxicology, Department of Emergency Medicine, UC San Diego Health, 200 W. Arbor Dr. #8676, San Diego, CA, 92103, USA
- California Poison Control System, San Diego, CA, USA
- VA San Diego Healthcare System, San Diego, CA, USA
| | - Henrik Galust
- Division of Medical Toxicology, Department of Emergency Medicine, UC San Diego Health, 200 W. Arbor Dr. #8676, San Diego, CA, 92103, USA
- California Poison Control System, San Diego, CA, USA
- VA San Diego Healthcare System, San Diego, CA, USA
| | - F Lee Cantrell
- Division of Medical Toxicology, Department of Emergency Medicine, UC San Diego Health, 200 W. Arbor Dr. #8676, San Diego, CA, 92103, USA
- California Poison Control System, San Diego, CA, USA
| | - Alicia Minns
- Division of Medical Toxicology, Department of Emergency Medicine, UC San Diego Health, 200 W. Arbor Dr. #8676, San Diego, CA, 92103, USA
- California Poison Control System, San Diego, CA, USA
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Telisnor G, DeRemer DL, Frimpong E, Agyare E, Allen J, Ricks-Santi L, Han B, George T, Rogers SC. Review of genetic and pharmacogenetic differences in cytotoxic and targeted therapies for pancreatic cancer in African Americans. J Natl Med Assoc 2023; 115:164-174. [PMID: 36801148 PMCID: PMC10639003 DOI: 10.1016/j.jnma.2023.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 12/16/2022] [Accepted: 01/24/2023] [Indexed: 02/19/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer mortality and the incidence is projected to increase by 2030. Despite recent advances in its treatment, African Americans have a 50-60% higher incidence and 30% higher mortality rate when compared to European Americans possibly resulting from differences in socioeconomic status, access to healthcare, and genetics. Genetics plays a role in cancer predisposition, response to cancer therapeutics (pharmacogenetics), and in tumor behavior, making some genes targets for oncologic therapeutics. We hypothesize that the germline genetic differences in predisposition, drug response, and targeted therapies also impact PDAC disparities. To demonstrate the impact of genetics and pharmacogenetics on PDAC disparities, a review of the literature was performed using PubMed with variations of the following keywords: pharmacogenetics, pancreatic cancer, race, ethnicity, African, Black, toxicity, and the FDA-approved drug names: Fluoropyrimidines, Topoisomerase inhibitors, Gemcitabine, Nab-Paclitaxel, Platinum agents, Pembrolizumab, PARP-inhibitors, and NTRK fusion inhibitors. Our findings suggest that the genetic profiles of African Americans may contribute to disparities related to FDA approved chemotherapeutic response for patients with PDAC. We recommend a strong focus on improving genetic testing and participation in biobank sample donations for African Americans. In this way, we can improve our current understanding of genes that influence drug response for patients with PDAC.
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Affiliation(s)
- Guettchina Telisnor
- College of Pharmacy, CaRE(2) Health Equity Center, University of Florida, Gainesville, FL, USA
| | - David L DeRemer
- Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Esther Frimpong
- Department of Pharmaceutical Sciences, College of Pharmacy, Florida Agricultural and Mechanical University, Tallahassee, FL, USA
| | - Edward Agyare
- Department of Pharmaceutical Sciences, College of Pharmacy, Florida Agricultural and Mechanical University, Tallahassee, FL, USA
| | - John Allen
- College of Pharmacy, CaRE(2) Health Equity Center, University of Florida, Gainesville, FL, USA
| | - Luisel Ricks-Santi
- Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Bo Han
- Department of Surgery, College of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Thomas George
- Division of Hematology and Oncology, College of Medicine, University of Florida, 600 SW Archer Road, PO BOX 100278, Gainesville, FL 32610- 0278, USA
| | - Sherise C Rogers
- Division of Hematology and Oncology, College of Medicine, University of Florida, 600 SW Archer Road, PO BOX 100278, Gainesville, FL 32610- 0278, USA.
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Cura Y, Pérez-Ramírez C, Sánchez-Martín A, Membrive-Jimenez C, Valverde-Merino MI, González-Flores E, Morales AJ. Influence of Single-Nucleotide Polymorphisms on Clinical Outcomes of Capecitabine-Based Chemotherapy in Colorectal Cancer Patients: A Systematic Review. Cancers (Basel) 2023; 15:cancers15061821. [PMID: 36980706 PMCID: PMC10046456 DOI: 10.3390/cancers15061821] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 03/06/2023] [Accepted: 03/14/2023] [Indexed: 03/19/2023] Open
Abstract
The aim of this systematic review was to provide a comprehensive overview of the literature published in the last decade on the association of single-nucleotide polymorphisms in genes involved in the pharmacodynamic and pharmacokinetic pathways of capecitabine with treatment outcomes among colorectal cancer patients. A systematic search of the literature published in the last 10 years was carried out in two databases (Medline and Scopus) using keywords related to the objective. Quality assessment of the studies included was performed using an assessment tool derived from the Strengthening the Reporting of Genetic Association (STREGA) statement. Thirteen studies were included in this systematic review. Genes involved in bioactivation, metabolism, transport, mechanism of action of capecitabine, DNA repair, and folate cycle were associated with toxicity. Meanwhile, genes related to DNA repair were associated with therapy effectiveness. This systematic review reveals that several SNPs other than the four DPYD variants that are screened in clinical practice could have an impact on treatment outcomes. These findings suggest the identification of future predictive biomarkers of effectiveness and toxicity in colorectal cancer patients treated with capecitabine. However, the evidence is sparse and requires further validation.
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Affiliation(s)
- Yasmin Cura
- Pharmacy Service, Pharmacogenetics Unit, Hospital Universitario Virgen de las Nieves, Avda. de las Fuerzas Armadas 2, 18004 Granada, Spain
| | - Cristina Pérez-Ramírez
- Department of Biochemistry and Molecular Biology II, José Mataix Institute of Nutrition and Food Technology, Center for Biomedical Research, Universidad de Granada, Avda. del Conocimiento s/n, 18016 Granada, Spain
- Correspondence:
| | - Almudena Sánchez-Martín
- Pharmacy Service, Pharmacogenetics Unit, Hospital Universitario Virgen de las Nieves, Avda. de las Fuerzas Armadas 2, 18004 Granada, Spain
| | - Cristina Membrive-Jimenez
- Pharmacy Service, Pharmacogenetics Unit, Hospital Universitario Virgen de las Nieves, Avda. de las Fuerzas Armadas 2, 18004 Granada, Spain
| | - María Isabel Valverde-Merino
- Pharmaceutical Care Research Group, Facultad de Farmacia, Universidad de Granada, Campus de la Cartuja, 18071 Granada, Spain
| | - Encarnación González-Flores
- Medical Oncology, Hospital Universitario Virgen de las Nieves, Avda. de las Fuerzas Armadas 2, 18004 Granada, Spain
- Biosanitary Research Institute of Granada, Ibs.Granada, Avda. de Madrid, 15, 18012 Granada, Spain
| | - Alberto Jiménez Morales
- Pharmacy Service, Pharmacogenetics Unit, Hospital Universitario Virgen de las Nieves, Avda. de las Fuerzas Armadas 2, 18004 Granada, Spain
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32
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Jia X, Zhang T, Sun J, Lin H, Bai T, Qiao Y, Li Y, Li G, Li G, Peng X, Zhang A. Rs11479 in Thymidine Phosphorylase Associated with Prognosis of Patients with Colorectal Cancer Who Received Capecitabine-Based Adjuvant Chemotherapy. Pharmgenomics Pers Med 2023; 16:277-289. [PMID: 37025557 PMCID: PMC10072144 DOI: 10.2147/pgpm.s397382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 02/17/2023] [Indexed: 04/03/2023] Open
Abstract
Objective Thymidine Phosphorylase (TYMP) gene was of potential significance in the process of colorectal cancer (CRC) development and played an important role in capecitabine metabolism. This study was to identify the association between TYMP polymorphism and prognosis of postoperative patients with CRC who received capecitabine-based adjuvant chemotherapy. Methods A total of 218 patients with CRC who were treated with surgical resection and capecitabine-based adjuvant chemotherapy were included in this study retrospectively. Peripheral blood and peripheral blood mononuclear cell (PBMC) specimen of the patients were collected for the genotyping of TYMP polymorphism and TYMP mRNA expression, respectively. Univariate analysis of genotypes and prognosis was carried out by Kaplan-Meier survival analysis, Cox regression analysis was adopted in multivariate analysis. The mRNA expression of TYMP according to genotype status was analyzed using non-parameter test. Results Prevalence of rs11479 in TYMP among the 218 patients exhibited that minor allele frequency of rs11479 was 0.20 (GG 141 cases, GA 68 cases and AA 9 cases), which was in accordance with Hardy-Weinberg equilibrium (P=0.825). Association analysis suggested that the median disease-free survival (DFS) of patients with GG genotype and GA/AA genotype was 3.1 and 6.1 years, respectively (P=0.004). Furthermore, the median overall survival of patients with GG genotype and GA/AA genotype was 5.0 and 7.0 years, respectively (P=0.033). Multivariate Cox regression analysis exhibited that rs11479 polymorphism was an independent factor for DFS (HR = 1.64, P=0.009). Additionally, of the 65 PBMC specimens, mRNA expression results indicated that patients with GA/AA genotypes conferred significantly higher mRNA expression of TYMP than that of patients with GG genotype (P<0.001). Conclusion Polymorphism rs11479 in TYMP gene might predict the prognosis of patients with CRC who received capecitabine-based adjuvant chemotherapy through mediation of the mRNA expression of TYMP. The conclusion of this study should be validated in prospective clinical trials subsequently.
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Affiliation(s)
- Xiongjie Jia
- Department of Gastrointestinal Surgery, Affiliated Hospital of Hebei University, Baoding, People’s Republic of China
| | - Tao Zhang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Hebei University, Baoding, People’s Republic of China
| | - Junjie Sun
- Department of Gastrointestinal Surgery, Affiliated Hospital of Hebei University, Baoding, People’s Republic of China
| | - Hengxue Lin
- Department of Gastrointestinal Surgery, Affiliated Hospital of Hebei University, Baoding, People’s Republic of China
| | - Tianliang Bai
- Department of Gastrointestinal Surgery, Affiliated Hospital of Hebei University, Baoding, People’s Republic of China
| | - Yating Qiao
- Department of Gastrointestinal Surgery, Affiliated Hospital of Hebei University, Baoding, People’s Republic of China
| | - Yaxin Li
- Department of Gastrointestinal Surgery, Affiliated Hospital of Hebei University, Baoding, People’s Republic of China
| | - Gang Li
- Department of Gastrointestinal Surgery, Affiliated Hospital of Hebei University, Baoding, People’s Republic of China
| | - Guicun Li
- Department of Gastrointestinal Surgery, Affiliated Hospital of Hebei University, Baoding, People’s Republic of China
| | - Xinyu Peng
- Department of Gastrointestinal Surgery, Affiliated Hospital of Hebei University, Baoding, People’s Republic of China
| | - Aimin Zhang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Hebei University, Baoding, People’s Republic of China
- Correspondence: Aimin Zhang; Xinyu Peng, Department of Gastrointestinal Surgery, Affiliated Hospital of Hebei University, No. 212 Yu-Hua East Road, Baoding City, Hebei Province, People’s Republic of China, Tel +863125983782, Email ;
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Trontzas IP, Rapti VE, Syrigos NK, Gomatou G, Lagou S, Kanellis G, Kotteas EA. Capecitabine-associated enterocolitis: Narrative literature review of a rare adverse event and a case presentation. J Chemother 2023; 35:63-71. [PMID: 35014596 DOI: 10.1080/1120009x.2021.2025316] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Capecitabine is an oral 5-fluorouracil prodrug with antimetabolite activity commonly used in advanced colorectal and breast cancer. It presents with a generally good toxicity profile and most of the adverse events can be managed effectively. Enterocolitis is a rare, under-reported, but potentially fatal adverse event associated with capecitabine use. To the best of our knowledge, there are 21 cases of capecitabine-related enterocolitis reported in the literature. We herein present a narrative literature review of enteritis/colitis cases associated with capecitabine use, with highlight to the most common clinical presentation, common imaging and microscopic findings and management approach. We furthermore present a case of severe capecitabine-related enteritis.
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Affiliation(s)
- Ioannis P Trontzas
- 3rd Department of Internal Medicine, Oncology Unit, Sotiria General Hospital, Athens School of Medicine, Athens, Greece
| | - Vasiliki E Rapti
- 3rd Department of Internal Medicine, Oncology Unit, Sotiria General Hospital, Athens School of Medicine, Athens, Greece
| | - Nikolaos K Syrigos
- 3rd Department of Internal Medicine, Oncology Unit, Sotiria General Hospital, Athens School of Medicine, Athens, Greece
| | - Georgia Gomatou
- 3rd Department of Internal Medicine, Oncology Unit, Sotiria General Hospital, Athens School of Medicine, Athens, Greece
| | - Styliani Lagou
- 3rd Department of Internal Medicine, Oncology Unit, Sotiria General Hospital, Athens School of Medicine, Athens, Greece
| | - George Kanellis
- Hematopathology Department, Evangelismos Hospital, Athens, Greece
| | - Elias A Kotteas
- 3rd Department of Internal Medicine, Oncology Unit, Sotiria General Hospital, Athens School of Medicine, Athens, Greece
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34
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Matte P, Ducreux M. Case Report: Vision Loss Induced by Capecitabine in Patient with Preexisting Left Eyes Blind. Case Rep Oncol 2023; 16:474-477. [PMID: 37497421 PMCID: PMC10368103 DOI: 10.1159/000530402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 03/22/2023] [Indexed: 07/28/2023] Open
Abstract
Capecitabine is an orally administered fluoropyrimidine carbamate antineoplastic agent, widely used to treat different tumor types. Eye toxicity is not well established with this type of drug. Here, we report the case of a 57-year-old man with a low rectal cancer whose vision decreased 3 weeks after starting a daily treatment of capecitabine and radiotherapy. After eliminating all other diagnoses, toxicity of antineoplastic agents remains the most likely hypothesis, making it the first case of vision loss induced by this capecitabine.
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Affiliation(s)
- Paul Matte
- Digestive Oncology Department, Institut Gustave Roussy, Villejuif, France
| | - Michel Ducreux
- Digestive Oncology Department, Institut Gustave Roussy, Villejuif, France
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35
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Shao T, Zhang Y, Liu J, Chen J, Shu Q, Shou L. Capecitabine-induced enterocolitis: a case report and pharmacogenetic profile. Pharmacogenomics 2022; 23:953-959. [PMID: 36382550 DOI: 10.2217/pgs-2022-0124] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Capecitabine is a widely-used antineoplastic drug, a prodrug to 5-fluorouracil which commonly induces gastrointestinal toxicity. Enterocolitis, as a rarely recognized gastrointestinal adverse effect (AE) of capecitabine, is potentially severe and usually results in antitumor treatment withdrawal. For the better management of severe AEs, pharmacogenetics is one promising field. Herein, we describe a case of capecitabine-induced enterocolitis presenting with severe diarrhea in order to improve recognition by clinicians. Moreover, we conduct a pharmacogenetic profile of the patient and review the current studies of gene polymorphisms of 5-fluorouracil-related diarrhea, hoping to offer a reference for further clinical pharmacogenetic practice in predicting capecitabine AEs showing diarrhea as the main symptom.
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Affiliation(s)
- Tianyu Shao
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, People's Republic of China
| | - Yao Zhang
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, People's Republic of China
| | - Jiaping Liu
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, People's Republic of China
| | - Jialu Chen
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, People's Republic of China
| | - Qijin Shu
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, People's Republic of China.,Department of Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310000, People's Republic of China
| | - Liumei Shou
- Department of Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310000, People's Republic of China
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36
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Compound Capecitabine Colon-Targeted Microparticle Prepared by Coaxial Electrospray for Treatment of Colon Tumors. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27175690. [PMID: 36080457 PMCID: PMC9457672 DOI: 10.3390/molecules27175690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 09/01/2022] [Accepted: 09/02/2022] [Indexed: 11/26/2022]
Abstract
To improve the antitumor effect of combined capecitabine (CAP) and osimertinib (OSI) therapy and quickly and efficiently reduce tumor volumes for preoperative chemotherapy, we designed a compound CAP colon-targeted microparticle (COPMP) prepared by coaxial electrospray. COPMP is a core–shell microparticle composed of a Eudragit S100 outer layer and a CAP/OSI-loaded PLGA core. In this study, we characterized its size distribution, drug loading (DL), encapsulation efficiency (EE), differential scanning calorimetry (DSC), Fourier transform infrared spectra (FTIR), in vitro release, formula ratio, cellular growth inhibition, and in vivo antitumor efficacy. COPMP is of spherical appearance with a size of 1.87 ± 0.23 μm. The DLs of CAP and OSI are 4.93% and 4.95%, respectively. The DSC showed that the phase state of CAP and OSI changed after encapsulation. The FTIR results indicated good compatibility between the drug and excipients. The release curve showed that CAP and OSI were released in a certain ratio. They were barely released prior to 2 h (pH 1.0), less than 50% was released between 3 and 5 h (pH 6.8), and sustained release of up to 80% occurred between 6 and 48 h (pH 7.4). CAP and OSI demonstrated a synergistic effect on HCT-116 cells. In a colon tumor model, the tumor inhibition rate after oral administration of COPMP reached 94% within one week. All the data suggested that COPMP promotes the sustained release of CAP and OSI in the colon, which provides a preoperative chemotherapy scheme for the treatment of colon cancer.
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A Systematic Review of Clinical Validated and Potential miRNA Markers Related to the Efficacy of Fluoropyrimidine Drugs. DISEASE MARKERS 2022; 2022:1360954. [PMID: 36051356 PMCID: PMC9427288 DOI: 10.1155/2022/1360954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 07/15/2022] [Accepted: 07/29/2022] [Indexed: 12/24/2022]
Abstract
Colorectal cancer (CRC) is becoming increasingly prevalent worldwide. Fluoropyrimidine drugs are the primary chemotherapy regimens in routine clinical practice of CRC. However, the survival rate of patients on fluoropyrimidine-based chemotherapy varies significantly among individuals. Biomarkers of fluoropyrimidine drugs'' efficacy are needed to implement personalized medicine. This review summarized fluoropyrimidine drug-related microRNA (miRNA) by affecting metabolic enzymes or showing the relevance of drug efficacy. We first outlined 42 miRNAs that may affect the metabolism of fluoropyrimidine drugs. Subsequently, we filtered another 41 miRNAs related to the efficacy of fluoropyrimidine drugs based on clinical trials. Bioinformatics analysis showed that most well-established miRNA biomarkers were significantly enriched in the cancer pathways instead of the fluoropyrimidine drug metabolism pathways. The result also suggests that the miRNAs screened from metastasis patients have a more critical role in cancer development than those from non-metastasis patients. There are five miRNAs shared between these two lists. The miR-21, miR-215, and miR-218 can suppress fluoropyrimidine drugs'' catabolism. The miR-326 and miR-328 can reduce the efflux of fluoropyrimidine drugs. These five miRNAs could jointly act by increasing intracellular levels of fluoropyrimidine drugs'' cytotoxic metabolites, leading to better chemotherapy responses. In conclusion, we demonstrated that the dynamic changes in the transcriptional regulation via miRNAs might play significant roles in the efficacy and toxicity of the fluoropyrimidine drug. The reported miRNA biomarkers would help evaluate the efficacy of fluoropyrimidine drug-based chemotherapy and improve the prognosis of colorectal cancer patients.
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Chen J, Duan Z, Liu Y, Fu R, Zhu C. Ginsenoside Rh4 Suppresses Metastasis of Esophageal Cancer and Expression of c-Myc via Targeting the Wnt/β-Catenin Signaling Pathway. Nutrients 2022; 14:nu14153042. [PMID: 35893895 PMCID: PMC9331240 DOI: 10.3390/nu14153042] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/16/2022] [Accepted: 07/17/2022] [Indexed: 02/01/2023] Open
Abstract
The metastasis of esophageal squamous cell carcinoma (ESCC) is a leading cause of death worldwide, however, it has a poor prognosis. Ginsenoside Rh4 is a rare saponin that has been shown to have potential antitumor effectiveness in ESCC. However, the utility of Rh4 in ESCC metastasis and its undiscovered mode of action has not yet been explored. In this study, we found that Rh4 could inhibit ESCC metastasis by regulating the Wnt/β-catenin signaling pathway and the level of c-Myc, which is an important transcription factor in cancer. In in vitro experiments, Rh4 could inhibit the migration and invasion of ESCC cells without affecting cell viability. In in vivo experiments, Rh4 restrained ESCC metastasis to the lymph nodes and lungs via the suppression of epithelial-mesenchymal transition (EMT). The Wnt agonist HLY78 promoted EMT and migration of ESCC cells, whereas treatment of Rh4 can attenuate the promotion effect of HLY78. The siRNA knocking out c-Myc can also significantly reduce the expression of EMT-related marker proteins. This study illustrates a new concept for further research on the mechanism of Rh4 in ESCC.
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Affiliation(s)
- Jun Chen
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, 229 North Taibai Road, Xi’an 710069, China; (J.C.); (Z.D.); (Y.L.); (R.F.)
- Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, 229 North Taibai Road, Xi’an 710069, China
- Biotech & Biomed Research Institute, Northwest University, 229 North Taibai Road, Xi’an 710069, China
| | - Zhiguang Duan
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, 229 North Taibai Road, Xi’an 710069, China; (J.C.); (Z.D.); (Y.L.); (R.F.)
- Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, 229 North Taibai Road, Xi’an 710069, China
- Biotech & Biomed Research Institute, Northwest University, 229 North Taibai Road, Xi’an 710069, China
| | - Yannan Liu
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, 229 North Taibai Road, Xi’an 710069, China; (J.C.); (Z.D.); (Y.L.); (R.F.)
- Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, 229 North Taibai Road, Xi’an 710069, China
- Biotech & Biomed Research Institute, Northwest University, 229 North Taibai Road, Xi’an 710069, China
| | - Rongzhan Fu
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, 229 North Taibai Road, Xi’an 710069, China; (J.C.); (Z.D.); (Y.L.); (R.F.)
- Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, 229 North Taibai Road, Xi’an 710069, China
- Biotech & Biomed Research Institute, Northwest University, 229 North Taibai Road, Xi’an 710069, China
| | - Chenhui Zhu
- Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, 229 North Taibai Road, Xi’an 710069, China; (J.C.); (Z.D.); (Y.L.); (R.F.)
- Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, 229 North Taibai Road, Xi’an 710069, China
- Biotech & Biomed Research Institute, Northwest University, 229 North Taibai Road, Xi’an 710069, China
- Correspondence: ; Tel./Fax: +86-29-8830-5118
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Bignucolo A, Scarabel L, Toffoli G, Cecchin E, De Mattia E. Predicting drug response and toxicity in metastatic colorectal cancer: the role of germline markers. Expert Rev Clin Pharmacol 2022; 15:689-713. [PMID: 35829762 DOI: 10.1080/17512433.2022.2101447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Despite the introduction of targeted agents leading to therapeutic advances, clinical management of patients with metastatic colorectal cancer (mCRC) is still challenged by significant interindividual variability in treatment outcomes, both in terms of toxicity and therapy efficacy. The study of germline genetic variants could help to personalize and optimize therapeutic approaches in mCRC. AREAS COVERED A systematic review of pharmacogenetic studies in mCRC patients published on PubMed between 2011 and 2021, evaluating the role of germline variants as predictive markers of toxicity and efficacy of drugs currently approved for treatment of mCRC, was perfomed. EXPERT OPINION Despite the large amount of pharmacogenetic data published to date, only a few genetic markers (i.e., DPYD and UGT1A1 variants) reached the clinical practice, mainly to prevent the toxic effects of chemotherapy. The large heterogeneity of available studies represents the major limitation in comparing results and identifying potential markers for clinical use, the role of which remains exploratory in most cases. However, the available published findings are an important starting point for future investigations. They highlighted new promising pharmacogenetic markers within the network of inflammatory and immune response signaling. In addition, the emerging role of previously overlooked rare variants has been pointed out.
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Affiliation(s)
- Alessia Bignucolo
- Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Via Franco Gallini 2, 33081 Aviano (PN), Italy
| | - Lucia Scarabel
- Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Via Franco Gallini 2, 33081 Aviano (PN), Italy
| | - Giuseppe Toffoli
- Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Via Franco Gallini 2, 33081 Aviano (PN), Italy
| | - Erika Cecchin
- Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Via Franco Gallini 2, 33081 Aviano (PN), Italy
| | - Elena De Mattia
- Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Via Franco Gallini 2, 33081 Aviano (PN), Italy
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Diao W, Yang B, Sun S, Wang A, Kou R, Ge Q, Shi M, Lian B, Sun T, Wu J, Bai J, Qu M, Wang Y, Yu W, Gao Z. PNA-Modified Liposomes Improve the Delivery Efficacy of CAPIRI for the Synergistic Treatment of Colorectal Cancer. Front Pharmacol 2022; 13:893151. [PMID: 35784721 PMCID: PMC9240350 DOI: 10.3389/fphar.2022.893151] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 05/09/2022] [Indexed: 01/10/2023] Open
Abstract
Tumor-associated antigen mucin 1 (MUC1) is highly expressed in colorectal cancer and is positively correlated with advanced stage at diagnosis and poor patient outcomes. The combination of irinotecan and capecitabine is standard chemotherapy for metastatic colorectal cancer and is known as XELIRI or CAPIRI, which significantly prolongs the progression-free survival and overall survival of colorectal cancer patients compared to a single drug alone. We previously reported that peanut agglutinin (PNA)-conjugated liposomes showed enhanced drug delivery efficiency to MUC1-positive liver cancer cells. In this study, we prepared irinotecan hydrochloride (IRI) and capecitabine (CAP)-coloaded liposomes modified by peanut agglutinin (IRI/CAP-PNA-Lips) to target MUC1-positive colorectal cancer. The results showed that IRI/CAP-PNA-Lips showed an enhanced ability to target MUC1-positive colorectal cancer cells compared to unmodified liposomes. Treatment with IRI/CAP-PNA-Lips also increased the proportion of apoptotic cells and inhibited the proliferation of colorectal cancer cells. The targeting specificity for tumor cells and the antitumor effects of PNA-modified liposomes were significantly increased in tumor-bearing mice with no severe cytotoxicity to normal tissues. These results suggest that PNA-modified liposomes could provide a new delivery strategy for the synergistic treatment of colorectal cancer with clinical chemotherapeutic agents.
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Affiliation(s)
- Wenbin Diao
- School of Life Science and Technology, Weifang Medical University, Weifang, China
- Shandong Universities Key Laboratory of Biopharmaceuticals, Weifang, China
| | - Ben Yang
- School of Life Science and Technology, Weifang Medical University, Weifang, China
- Shandong Universities Key Laboratory of Biopharmaceuticals, Weifang, China
| | - Sipeng Sun
- School of Life Science and Technology, Weifang Medical University, Weifang, China
- Shandong Universities Key Laboratory of Biopharmaceuticals, Weifang, China
| | - Anping Wang
- School of Life Science and Technology, Weifang Medical University, Weifang, China
- Shandong Universities Key Laboratory of Biopharmaceuticals, Weifang, China
| | - Rongguan Kou
- School of Life Science and Technology, Weifang Medical University, Weifang, China
| | - Qianyun Ge
- School of Life Science and Technology, Weifang Medical University, Weifang, China
- Shandong Universities Key Laboratory of Biopharmaceuticals, Weifang, China
| | - Mengqi Shi
- School of Life Science and Technology, Weifang Medical University, Weifang, China
- Shandong Universities Key Laboratory of Biopharmaceuticals, Weifang, China
| | - Bo Lian
- School of Life Science and Technology, Weifang Medical University, Weifang, China
- Shandong Universities Key Laboratory of Biopharmaceuticals, Weifang, China
| | - Tongyi Sun
- School of Life Science and Technology, Weifang Medical University, Weifang, China
- Shandong Universities Key Laboratory of Biopharmaceuticals, Weifang, China
| | - Jingliang Wu
- School of Life Science and Technology, Weifang Medical University, Weifang, China
- Shandong Universities Key Laboratory of Biopharmaceuticals, Weifang, China
| | - Jingkun Bai
- School of Life Science and Technology, Weifang Medical University, Weifang, China
- Shandong Universities Key Laboratory of Biopharmaceuticals, Weifang, China
| | - Meihua Qu
- Translational Medical Center, Second People’s Hospital of Weifang, Weifang, China
| | - Yubing Wang
- School of Life Science and Technology, Weifang Medical University, Weifang, China
- Shandong Universities Key Laboratory of Biopharmaceuticals, Weifang, China
- *Correspondence: Yubing Wang, ; Wenjing Yu, ; Zhiqin Gao,
| | - Wenjing Yu
- School of Life Science and Technology, Weifang Medical University, Weifang, China
- Shandong Universities Key Laboratory of Biopharmaceuticals, Weifang, China
- *Correspondence: Yubing Wang, ; Wenjing Yu, ; Zhiqin Gao,
| | - Zhiqin Gao
- School of Life Science and Technology, Weifang Medical University, Weifang, China
- Shandong Universities Key Laboratory of Biopharmaceuticals, Weifang, China
- *Correspondence: Yubing Wang, ; Wenjing Yu, ; Zhiqin Gao,
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Trilla-Fuertes L, Gámez-Pozo A, Lumbreras-Herrera MI, López-Vacas R, Heredia-Soto V, Ghanem I, López-Camacho E, Zapater-Moros A, Miguel M, Peña-Burgos EM, Palacios E, de Uribe M, Guerra L, Dittmann A, Mendiola M, Fresno Vara JÁ, Feliu J. Identification of Carcinogenesis and Tumor Progression Processes in Pancreatic Ductal Adenocarcinoma Using High-Throughput Proteomics. Cancers (Basel) 2022; 14:cancers14102414. [PMID: 35626021 PMCID: PMC9139847 DOI: 10.3390/cancers14102414] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/05/2022] [Accepted: 05/11/2022] [Indexed: 11/16/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with an overall 5-year survival rate of just 5%. A better understanding of the carcinogenesis processes and the mechanisms of the progression of PDAC is mandatory. Fifty-two PDAC patients treated with surgery and adjuvant therapy, with available primary tumors, normal tissue, preneoplastic lesions (PanIN), and/or lymph node metastases, were selected for the study. Proteins were extracted from small punches and analyzed by LC-MS/MS using data-independent acquisition. Proteomics data were analyzed using probabilistic graphical models, allowing functional characterization. Comparisons between groups were made using linear mixed models. Three proteomic tumor subtypes were defined. T1 (32% of patients) was related to adhesion, T2 (34%) had metabolic features, and T3 (34%) presented high splicing and nucleoplasm activity. These proteomics subtypes were validated in the PDAC TCGA cohort. Relevant biological processes related to carcinogenesis and tumor progression were studied in each subtype. Carcinogenesis in the T1 subtype seems to be related to an increase of adhesion and complement activation node activity, whereas tumor progression seems to be related to nucleoplasm and translation nodes. Regarding the T2 subtype, it seems that metabolism and, especially, mitochondria act as the motor of cancer development. T3 analyses point out that nucleoplasm, mitochondria and metabolism, and extracellular matrix nodes could be involved in T3 tumor carcinogenesis. The identified processes were different among proteomics subtypes, suggesting that the molecular motor of the disease is different in each subtype. These differences can have implications for the development of future tailored therapeutic approaches for each PDAC proteomics subtype.
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Affiliation(s)
- Lucía Trilla-Fuertes
- Molecular Oncology & Pathology Laboratory, Instituto de Genética Médica y Molecular-INGEMM, Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, Spain; (L.T.-F.); (A.G.-P.); (M.I.L.-H.); (R.L.-V.); (J.Á.F.V.)
| | - Angelo Gámez-Pozo
- Molecular Oncology & Pathology Laboratory, Instituto de Genética Médica y Molecular-INGEMM, Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, Spain; (L.T.-F.); (A.G.-P.); (M.I.L.-H.); (R.L.-V.); (J.Á.F.V.)
| | - María Isabel Lumbreras-Herrera
- Molecular Oncology & Pathology Laboratory, Instituto de Genética Médica y Molecular-INGEMM, Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, Spain; (L.T.-F.); (A.G.-P.); (M.I.L.-H.); (R.L.-V.); (J.Á.F.V.)
| | - Rocío López-Vacas
- Molecular Oncology & Pathology Laboratory, Instituto de Genética Médica y Molecular-INGEMM, Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, Spain; (L.T.-F.); (A.G.-P.); (M.I.L.-H.); (R.L.-V.); (J.Á.F.V.)
| | - Victoria Heredia-Soto
- Molecular Pathology and Therapeutic Targets Group, Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, Spain; (V.H.-S.); (M.M.); (M.M.)
- Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII, 28029 Madrid, Spain
| | - Ismael Ghanem
- Medical Oncology Service, Hospital Universitario La Paz, 28046 Madrid, Spain;
| | | | | | - María Miguel
- Molecular Pathology and Therapeutic Targets Group, Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, Spain; (V.H.-S.); (M.M.); (M.M.)
| | - Eva M. Peña-Burgos
- Pathology Department, Hospital Universitario La Paz, 28046 Madrid, Spain; (E.M.P.-B.); (E.P.); (M.d.U.); (L.G.)
| | - Elena Palacios
- Pathology Department, Hospital Universitario La Paz, 28046 Madrid, Spain; (E.M.P.-B.); (E.P.); (M.d.U.); (L.G.)
| | - Marta de Uribe
- Pathology Department, Hospital Universitario La Paz, 28046 Madrid, Spain; (E.M.P.-B.); (E.P.); (M.d.U.); (L.G.)
| | - Laura Guerra
- Pathology Department, Hospital Universitario La Paz, 28046 Madrid, Spain; (E.M.P.-B.); (E.P.); (M.d.U.); (L.G.)
| | - Antje Dittmann
- Functional Genomics Center Zurich, University of Zurich/ETH Zurich, 8057 Zurich, Switzerland;
| | - Marta Mendiola
- Molecular Pathology and Therapeutic Targets Group, Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, Spain; (V.H.-S.); (M.M.); (M.M.)
| | - Juan Ángel Fresno Vara
- Molecular Oncology & Pathology Laboratory, Instituto de Genética Médica y Molecular-INGEMM, Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, Spain; (L.T.-F.); (A.G.-P.); (M.I.L.-H.); (R.L.-V.); (J.Á.F.V.)
- Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII, 28029 Madrid, Spain
| | - Jaime Feliu
- Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII, 28029 Madrid, Spain
- Medical Oncology Service, Hospital Universitario La Paz, 28046 Madrid, Spain;
- Cátedra UAM-ANGEM, Faculty of Medicine, Universidad Autónoma de Madrid, 28046 Madrid, Spain
- Correspondence:
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Yang Q, Chen C, Ran J. Capecitabine-induced severe diabetes and hypokalemia: a case report. J Med Case Rep 2022; 16:163. [PMID: 35462530 PMCID: PMC9036807 DOI: 10.1186/s13256-022-03392-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 03/28/2022] [Indexed: 12/03/2022] Open
Abstract
Background Capecitabine is widely used in chemotherapy for breast, colorectal, and gastric cancers. The frequent adverse reactions of capecitabine mainly include gastrointestinal side effects, anemia, and cardiovascular toxicity. Here, we report a rare case of severe hyperglycemia and hypokalemia during long-term treatment with capecitabine. Case presentation A 48-year-old Chinese female was hospitalized with the complaint of breathlessness and weakness after activity, for 1 month. Her past history is significant for a diagnosis of right-sided breast cancer 7 years ago. She underwent right mastectomy, following which capecitabine was started 1.5 years prior to the current admission as part of her primary treatment at the discovery of systemic osseous metastasis. Her fasting plasma glucose and hemoglobin A1c levels were quite normal 7 months ago but increased to 15.3 mmol/L and 11.2%, respectively, at the present admission. Her serum potassium level was as low as 2.5 mmol/L. Plasma autoantibodies related to islets and insulin were all negative. Capecitabine was discontinued, and an insulin pump and potassium supplement were given after admission. Her blood sugar and potassium levels returned to their normal ranges soon. Self-injection of insulin was withdrawn completely at 2 months after discharge, and no oral hypoglycemic agents were added. Her plasma glucose and electrolyte levels were at normal levels at her 1-year follow-up. Conclusion Glucose intolerance and hypokalemia may be rare but serious adverse effects during long-term chemotherapy with capecitabine.
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Zhang S, Fan S, Wang Z, Hou W, Liu T, Yoshida S, Yang S, Zheng H, Shen Z. Capecitabine Regulates HSP90AB1 Expression and Induces Apoptosis via Akt/SMARCC1/AP-1/ROS Axis in T Cells. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:1012509. [PMID: 35368874 PMCID: PMC8970866 DOI: 10.1155/2022/1012509] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 03/10/2022] [Indexed: 11/17/2022]
Abstract
Transplant oncology is a newly emerging discipline integrating oncology, transplant medicine, and surgery and has brought malignancy treatment into a new era via transplantation. In this context, obtaining a drug with both immunosuppressive and antitumor effects can take into account the dual needs of preventing both transplant rejection and tumor recurrence in liver transplantation patients with malignancies. Capecitabine (CAP), a classic antitumor drug, has been shown to induce reactive oxygen species (ROS) production and apoptosis in tumor cells. Meanwhile, we have demonstrated that CAP can induce ROS production and apoptosis in T cells to exert immunosuppressive effects, but its underlying molecular mechanism is still unclear. In this study, metronomic doses of CAP were administered to normal mice by gavage, and the spleen was selected for quantitative proteomic and phosphoproteomic analysis. The results showed that CAP significantly reduced the expression of HSP90AB1 and SMARCC1 in the spleen. It was subsequently confirmed that CAP also significantly reduced the expression of HSP90AB1 and SMARCC1 and increased ROS and apoptosis levels in T cells. The results of in vitro experiments showed that HSP90AB1 knockdown resulted in a significant decrease in p-Akt, SMARCC1, p-c-Fos, and p-c-Jun expression levels and a significant increase in ROS and apoptosis levels. HSP90AB1 overexpression significantly inhibited CAP-induced T cell apoptosis by increasing the p-Akt, SMARCC1, p-c-Fos, and p-c-Jun expression levels and reducing the ROS level. In conclusion, HSP90AB1 is a key target of CAP-induced T cell apoptosis via Akt/SMARCC1/AP-1/ROS axis, which provides a novel understanding of CAP-induced T cell apoptosis and lays the experimental foundation for further exploring CAP as an immunosuppressant with antitumor effects to optimize the medication regimen for transplantation patients.
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Affiliation(s)
- Sai Zhang
- School of Medicine, Nankai University, Tianjin, China
- Organ Transplant Department, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | - Shunli Fan
- First Central Clinical Institute, Tianjin Medical University, Tianjin, China
| | - Zhenglu Wang
- Organ Transplant Department, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin First Central Hospital, Tianjin, China
| | - Wen Hou
- National Health Commission's Key Laboratory for Critical Care Medicine, Tianjin, China
| | - Tao Liu
- National Health Commission's Key Laboratory for Critical Care Medicine, Tianjin, China
| | - Sei Yoshida
- Research Institute of Transplant Medicine, Nankai University, Tianjin, China
| | - Shuang Yang
- Research Institute of Transplant Medicine, Nankai University, Tianjin, China
| | - Hong Zheng
- Organ Transplant Department, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin First Central Hospital, Tianjin, China
- Research Institute of Transplant Medicine, Nankai University, Tianjin, China
- Tianjin Key Laboratory for Organ Transplantation, Tianjin, China
| | - Zhongyang Shen
- Organ Transplant Department, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
- Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin First Central Hospital, Tianjin, China
- National Health Commission's Key Laboratory for Critical Care Medicine, Tianjin, China
- Research Institute of Transplant Medicine, Nankai University, Tianjin, China
- Tianjin Key Laboratory for Organ Transplantation, Tianjin, China
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Chemotherapy of Capecitabine plus Temozolomide for Refractory Pituitary Adenoma after Tumor Resection and Its Impact on Serum Prolactin, IGF-1, and Growth Hormone. JOURNAL OF ONCOLOGY 2022; 2022:8361775. [PMID: 35356252 PMCID: PMC8959954 DOI: 10.1155/2022/8361775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/11/2022] [Accepted: 02/14/2022] [Indexed: 11/17/2022]
Abstract
Objective To investigate the efficiency of capecitabine (CAP) plus temozolomide (TEM) in refractory pituitary adenoma after tumor resection and its impact on serum prolactin (PRL), insulin-like growth factor 1 (IGF-1), and growth hormone (GH) levels. Methods From January 2017 to January 2020, 80 patients assessed for eligibility receiving transsphenoidal tumor resection for refractory pituitary adenoma in the Department of Neurosurgery of our hospital were recruited. They were randomly distributed at a ratio of 1 : 1 via the random number table method to receive either bromocriptine and TEM (control group) or bromocriptine plus combination chemotherapy of TEM and CAP (study group). The two groups were compared in terms of clinical efficacy and serum levels of PRL, IGF-1, and GH. Results The objective response rate (ORR) was 87.50% and 67.50% in the study group and the control group, respectively (P=0.032). Before treatment, two groups had similar levels of PRL, IGF-1, and GH. After treatment, PRL levels in the study group were lower than that in the control group (278.35 ± 39.25 versus 326.35 ± 42.45, P < 0.001). Compared with the control group, IGF-1 levels in the study group were also lower (311.78 ± 28.82 versus 364.35 ± 31.35, P < 0.001). The study group presented markedly lower levels of thyroid-stimulating hormone (TSH) and higher serum levels of free thyroxine-4 (FT-4) and adrenocorticotropic hormone (ACTH) versus the control group (P < 0.05). The incidence of adverse events was comparable between the study group (30.0%) and the control group (22.5%) (P > 0.05). All eligible patients had similar progression-free survival (PFS) after chemotherapy. Conclusion For patients with refractory pituitary adenoma, the combination chemotherapy of CAP and TEM significantly improves clinical outcomes and corrects hormonal disturbances, with a good safety profile, but its long-term efficacy requires further investigation.
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Tian J, Zhang J, Yang Z, Feng S, Li S, Ren S, Shi J, Hou X, Xue X, Yang B, Xu H, Guo J. Genetic Epidemiology of Medication Safety and Efficacy Related Variants in the Central Han Chinese Population With Whole Genome Sequencing. Front Pharmacol 2022; 12:790832. [PMID: 35280256 PMCID: PMC8906509 DOI: 10.3389/fphar.2021.790832] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 12/14/2021] [Indexed: 12/22/2022] Open
Abstract
Medication safety and efficacy-related pharmacogenomic research play a critical role in precision medicine. This study comprehensively analyzed the pharmacogenomic profiles of the central Han Chinese population in the context of medication safety and efficacy and compared them with other global populations. The ultimate goal is to improve medical treatment guidelines. We performed whole-genome sequencing in 487 Han Chinese individuals and investigated the allele frequencies of pharmacogenetic variants in 1,731 drug response-related genes. We identified 2,139 (81.18%) previously reported variants in our population with annotations in the PharmGKB database. The allele frequencies of these 2,139 clinical-related variants were similar to those in other East Asian populations but different from those in other global populations. We predicted the functional effects of nonsynonymous variants in the 1,731 pharmacogenes and identified 1,281 novel and 4,442 previously reported deleterious variants. Of the 1,281 novel deleterious variants, five are common variants with an allele frequency >5%, and the rest are rare variants with an allele frequency <5%. Of the 4,442 known deleterious variants, the allele frequencies were found to differ from those in other populations, of which 146 are common variants. In addition, we found many variants in non-coding regions, the functions of which require further investigation. This study compiled a large amount of data on pharmacogenomic variants in the central Han Chinese population. At the same time, it provides insight into the role of pharmacogenomic variants in clinical medication safety and efficacy.
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Affiliation(s)
- Junbo Tian
- BGI College and Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Jing Zhang
- Precision Medicine Center, Academy of Medical Science, Zhengzhou University, Zhengzhou, China
| | - Zengguang Yang
- Precision Medicine Center, Academy of Medical Science, Zhengzhou University, Zhengzhou, China
| | - Shuaisheng Feng
- Precision Medicine Center, Academy of Medical Science, Zhengzhou University, Zhengzhou, China
| | - Shujuan Li
- Department of Pharmacy, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shiqi Ren
- BGI College and Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Jianxiang Shi
- BGI College and Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Xinyue Hou
- Precision Medicine Center, Academy of Medical Science, Zhengzhou University, Zhengzhou, China
| | - Xia Xue
- Precision Medicine Center, Academy of Medical Science, Zhengzhou University, Zhengzhou, China
| | - Bei Yang
- School of Information Engineering, Zhengzhou University, Zhengzhou, China
| | - Hongen Xu
- Precision Medicine Center, Academy of Medical Science, Zhengzhou University, Zhengzhou, China
| | - Jiancheng Guo
- BGI College and Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China.,Precision Medicine Center, Academy of Medical Science, Zhengzhou University, Zhengzhou, China.,The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Lohan-Codeço M, Barambo-Wagner ML, Nasciutti LE, Ribeiro Pinto LF, Meireles Da Costa N, Palumbo A. Molecular mechanisms associated with chemoresistance in esophageal cancer. Cell Mol Life Sci 2022; 79:116. [PMID: 35113247 PMCID: PMC11073146 DOI: 10.1007/s00018-022-04131-6] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 12/23/2021] [Accepted: 12/27/2021] [Indexed: 02/07/2023]
Abstract
Esophageal cancer (EC) is one of the most incident and lethal tumors worldwide. Although surgical resection is an important approach in EC treatment, late diagnosis, metastasis and recurrence after surgery have led to the management of adjuvant and neoadjuvant therapies over the past few decades. In this scenario, 5-fluorouracil (5-FU) and cisplatin (CISP), and more recently paclitaxel (PTX) and carboplatin (CBP), have been traditionally used in EC treatment. However, chemoresistance to these agents along EC therapeutic management represents the main obstacle to successfully treat this malignancy. In this sense, despite the fact that most of chemotherapy drugs were discovered several decades ago, in many cases, including EC, they still represent the most affordable and widely employed treatment approach for these tumors. Therefore, this review summarizes the main mechanisms through which the response to the most widely chemotherapeutic agents used in EC treatment is impaired, such as drug metabolism, apoptosis resistance, cancer stem cells (CSCs), cell cycle, autophagy, energetic metabolism deregulation, tumor microenvironment and epigenetic modifications.
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Affiliation(s)
- Matheus Lohan-Codeço
- Laboratório de Interações Celulares, Instituto de Ciências Biomédicas, Programa de Pesquisa em Biologia Celular e do Desenvolvimento, Universidade Federal do Rio de Janeiro, Prédio do Centro de Ciências da Saúde-Cidade Universitária, Ilha do Fundão, Rua César Pernetta, 1766 (LS.3.01), Rio de Janeiro, RJ, Brasil
| | - Maria Luísa Barambo-Wagner
- Programa de Carcinogênese Molecular Coordenação de Pesquisa, Instituto Nacional de Câncer-INCA, Rua André Cavalcanti, 37-6ºandar-Centro, Rio de Janeiro, RJ, 20231-050, Brazil
| | - Luiz Eurico Nasciutti
- Laboratório de Interações Celulares, Instituto de Ciências Biomédicas, Programa de Pesquisa em Biologia Celular e do Desenvolvimento, Universidade Federal do Rio de Janeiro, Prédio do Centro de Ciências da Saúde-Cidade Universitária, Ilha do Fundão, Rua César Pernetta, 1766 (LS.3.01), Rio de Janeiro, RJ, Brasil
| | - Luis Felipe Ribeiro Pinto
- Programa de Carcinogênese Molecular Coordenação de Pesquisa, Instituto Nacional de Câncer-INCA, Rua André Cavalcanti, 37-6ºandar-Centro, Rio de Janeiro, RJ, 20231-050, Brazil
| | - Nathalia Meireles Da Costa
- Programa de Carcinogênese Molecular Coordenação de Pesquisa, Instituto Nacional de Câncer-INCA, Rua André Cavalcanti, 37-6ºandar-Centro, Rio de Janeiro, RJ, 20231-050, Brazil.
| | - Antonio Palumbo
- Laboratório de Interações Celulares, Instituto de Ciências Biomédicas, Programa de Pesquisa em Biologia Celular e do Desenvolvimento, Universidade Federal do Rio de Janeiro, Prédio do Centro de Ciências da Saúde-Cidade Universitária, Ilha do Fundão, Rua César Pernetta, 1766 (LS.3.01), Rio de Janeiro, RJ, Brasil.
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Abstract
Chemotherapy, as an important clinical treatment, has greatly enhanced survival in cancer patients, but the side effects and long-term sequelae bother both patients and clinicians. 5-Fluorouracil (5-FU) has been widely used as a chemotherapeutic agent in the clinical treatment of various cancers, but several studies showed its adverse effects on reproduction. Reproductive toxicity of 5-FU often associates with developmental block, malformation and ovarian damage in the females. In males, 5-FU administration alters the morphology of sexual organs, the levels of reproductive endocrine hormones and the progression of spermatogenesis, ultimately reducing sperm numbers. Mechanistically, 5-FU exerts its effect through incorporating the active metabolites into nucleic acids directly, or inhibiting thymidylate synthase to disrupt the function of DNA and RNA, leading to profound effects on cellular metabolism and viability. However, some studies suggested that the toxicity of 5-FU on reproduction is reversible and certain drugs used in combination with 5-FU during chemotherapy could protect reproductive systems from 5-FU damage both in females and males. Herein, we summarise the recent findings and discuss underlying mechanisms of the 5-FU-induced reproductive toxicity, providing a reference for future research and clinical treatments.
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Shao M, Jiang C, Yu C, Jia H, Wang Y, Mao X. Capecitabine inhibits epithelial‑to‑mesenchymal transition and proliferation of colorectal cancer cells by mediating the RANK/RANKL pathway. Oncol Lett 2022; 23:96. [PMID: 35154427 PMCID: PMC8822391 DOI: 10.3892/ol.2022.13216] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 10/06/2021] [Indexed: 11/08/2022] Open
Abstract
Colorectal cancer (CRC) is the third most prevalent malignancy globally. Capecitabine is an important form of chemotherapy for colorectal cancer. The present study aims to investigate the underlying mechanism of action of the drug in CRC cells. In the present study, 50 pairs of CRC and adjacent normal tissues were collected, and CRC cell lines (SW480, SW620, HT29, LOVO and HCT116) and NCM460 colonic epithelial cells were also purchased and used. Western blotting was used to measure the expression levels of proteins involved in the receptor activator of nuclear factor-κB (RANK)/receptor activator of nuclear factor-κB ligand (RANKL) pathway and epithelial-to-mesenchymal transition (EMT), including RANK, RANKL, osteoprotegerin (OPG), E-cadherin, vimentin and N-cadherin. Proliferation and migration were measured using MTT, Cell Counting Kit-8, EdU, Transwell and wound healing assays, respectively. In the present study, it was found that the RANK/RANKL pathway was activated in cancer tissues and cells. Additionally, it was observed that capecitabine treatment reduced the protein expression of RANK, RANKL and OPG in HT29 cells, suggesting that capecitabine has a repressive effect on the RANK/RANKL pathway. Furthermore, functional experiments revealed that the proliferative ability and the EMT process observed in HT29 cells were inhibited after they were treated with capecitabine or transfected with si-RANK. Rescue assays were then performed, which revealed that the promotion of RANK via transfection of cells with 50 nM pcDNA3.1-RANK reversed the inhibitory effects of capecitabine on HT29 cell proliferation and EMT. These findings suggest that the regulatory role of capecitabine is at least partially mediated through the RANK/RANKL pathway in colorectal cancer. The present study demonstrated that capecitabine-induced repression of CRC is exerted by inhibiting the RANK/RANKL pathway, where this new mechanism potentially provides a novel therapeutic target.
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Affiliation(s)
- Minghai Shao
- Department of Radiation Oncology, Key Laboratory of Minimally Invasive Techniques and Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang 317000, P.R. China
| | - Caiping Jiang
- Department of Radiation Oncology, Key Laboratory of Minimally Invasive Techniques and Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang 317000, P.R. China
| | - Changhui Yu
- Department of Radiation Oncology, Key Laboratory of Minimally Invasive Techniques and Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang 317000, P.R. China
| | - Haijian Jia
- Department of Radiation Oncology, Key Laboratory of Minimally Invasive Techniques and Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang 317000, P.R. China
| | - Yanli Wang
- Department of Radiation Oncology, Key Laboratory of Minimally Invasive Techniques and Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang 317000, P.R. China
| | - Xinli Mao
- Department of Gastroenterology, Key Laboratory of Minimally Invasive Techniques and Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang 317000, P.R. China
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Xu J, Lin Z, Chen J, Zhang J, Li W, Zhang R, Xing J, Ye Z, Liu X, Gao Q, Chen X, Zhai J, Yao H, Li M, Wei H. Milk and Egg Are Risk Factors for Adverse Effects of Capecitabine-Based Chemotherapy in Chinese Colorectal Cancer Patients. Integr Cancer Ther 2022; 21:15347354221105485. [PMID: 35686441 PMCID: PMC9189551 DOI: 10.1177/15347354221105485] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background: Chemotherapy-induced adverse effects (CIAEs) remain a challenging problem due to their high incidences and negative impacts on treatment in Chinese colorectal cancer (CRC) patients. We aimed to identify risk factors and predictive markers for CIAEs using food/nutrition data in CRC patients receiving post-operative capecitabine-based chemotherapy. Methods: Food/nutrition data from 130 Chinese CRC patients were analyzed. Univariate and multivariate analyses were used to identify CIAE-related food/nutrition factors. Prediction models were constructed based on the combination of these factors. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the discrimination ability of models. Results: A total of 20 food/nutrition factors associated with CIAEs were identified in the univariate analysis after adjustments for total energy and potential confounding factors. Based on multivariate analysis, we found that, among these factors, dessert, eggs, poultry, and milk were associated with several CIAEs. Most importantly, poultry was an overall protective factor; milk and egg were risk factors for hand-foot syndrome (HFS) and bone marrow suppression (BMS), respectively. Developed multivariate models in predicting grade 1 to 3 CIAEs and grade 2/3 CIAEs both had good discrimination (AUROC values from 0.671 to 0.778, 0.750 to 0.946 respectively), which had potential clinical application value in the early prediction of CIAEs, especially for more severe CIAEs. Conclusions: Our findings suggest that patients with high milk and egg intakes should be clinically instructed to control their corresponding dietary intake to reduce the likelihood of developing HFS and BMS during capecitabine-based chemotherapy, respectively. Trial registration: ClinicalTrials.gov Identifier: NCT03030508.
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Affiliation(s)
- Jinrong Xu
- Taiyuan Institute of Technology, Taiyuan, Shanxi, China
| | - Zeshuai Lin
- Shanxi Medical University, Taiyuan, Shanxi, China.,Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Jiani Chen
- Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Jian Zhang
- Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | | | - Rui Zhang
- Chengdu Medical College, Chengdu, China
| | - Jin Xing
- Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Zhihuan Ye
- Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Xiaoping Liu
- Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Qianmin Gao
- Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Xintao Chen
- Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Jingwen Zhai
- Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Houshan Yao
- Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Mingming Li
- Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Hua Wei
- Second Affiliated Hospital of Naval Medical University, Shanghai, China.,905th Hospital of PLA Navy, Naval Medical University, Shanghai, China
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Comparison of Anticancer Drug Toxicities: Paradigm Shift in Adverse Effect Profile. Life (Basel) 2021; 12:life12010048. [PMID: 35054441 PMCID: PMC8777973 DOI: 10.3390/life12010048] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/17/2021] [Accepted: 12/24/2021] [Indexed: 02/06/2023] Open
Abstract
The inception of cancer treatment with chemotherapeutics began in the 1940s with nitrogen mustards that were initially employed as weapons in World War II. Since then, treatment options for different malignancies have evolved over the period of last seventy years. Until the late 1990s, all the chemotherapeutic agents were small molecule chemicals with a highly nonspecific and severe toxicity spectrum. With the landmark approval of rituximab in 1997, a new horizon has opened up for numerous therapeutic antibodies in solid and hematological cancers. Although this transition to large molecules improved the survival and quality of life of cancer patients, this has also coincided with the change in adverse effect patterns. Typically, the anticancer agents are fraught with multifarious adverse effects that negatively impact different organs of cancer patients, which ultimately aggravate their sufferings. In contrast to the small molecules, anticancer antibodies are more targeted toward cancer signaling pathways and exhibit fewer side effects than traditional small molecule chemotherapy treatments. Nevertheless, the interference with the immune system triggers serious inflammation- and infection-related adverse effects. The differences in drug disposition and interaction with human basal pathways contribute to this paradigm shift in adverse effect profile. It is critical that healthcare team members gain a thorough insight of the adverse effect differences between the agents discovered during the last twenty-five years and before. In this review, we summarized the general mechanisms and adverse effects of small and large molecule anticancer drugs that would further our understanding on the toxicity patterns of chemotherapeutic regimens.
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