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Wang X, Li S, Wang Z, Kang B, Yan H. The Co-Delivery of Natural Products and Small RNAs for Cancer Therapy: A Review. Molecules 2025; 30:1495. [PMID: 40286130 PMCID: PMC11990496 DOI: 10.3390/molecules30071495] [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: 01/28/2025] [Revised: 03/23/2025] [Accepted: 03/26/2025] [Indexed: 04/29/2025] Open
Abstract
This review summarizes the research progress in the co-delivery of natural products (NPs) and small RNAs in cancer therapy. NPs such as paclitaxel, camptothecin, and curcumin possess multi-target antitumor effects, but their applications are limited by drug resistance and non-specific distribution. Small RNAs can achieve precise antitumor effects through gene regulation, yet their delivery efficiency is low, and they are prone to degradation by nucleases. Nanomaterial-based drug delivery systems (nano-DDSs) provide an efficient platform for the co-delivery of both, which can enhance the targeting of their delivery and improve the synergistic antitumor effects simultaneously. The mechanisms of the antitumor action of natural compounds and small RNAs, the design and application of nanocarriers, and the latest research progress in co-delivery systems are introduced in detail in this paper. The application prospects of the co-delivery of natural compounds and small RNAs in cancer therapy are also discussed.
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Affiliation(s)
| | | | | | | | - Hong Yan
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China; (X.W.); (S.L.); (Z.W.); (B.K.)
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Mandal G, Umar M, Lv R, Guo R, Ge T, Awais M, Yang S, Hasan MSU, Liu J. Facile synthesis of plasmonic BP@Au nanomatrix for sensitive detection of irinotecan and its active SN-38 metabolite via laser desorption/ionization mass spectrometry. Mikrochim Acta 2025; 192:98. [PMID: 39836307 DOI: 10.1007/s00604-024-06881-5] [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: 09/17/2024] [Accepted: 12/05/2024] [Indexed: 01/22/2025]
Abstract
A new methodology is presented for the rapid, specific, and sensitive detection of irinotecan (CPT-11), a chemotherapeutic agent utilized in the treatment of cancer, along with its metabolically active derivative, SN-38, via laser desorption/ionization mass spectrometry (LDI MS). The method includes the detection of camptothecin (CPT), which can be utilized as an internal standard for the quantitative assessment of both CPT-11 and SN-38 in mouse serum. The approach utilizes a plasmonic two-dimensional (2D) black phosphorus nanosheet (BPN)-gold nanomatrix (BP@Au) in LDI MS. The experimental results demonstrated that the BP@Au nanomatrix outperformed the standard organic matrices (SA, CHCA, and DHB) in detecting irinotecan and its active metabolite with improved specificity and sensitivity, crucial factors for applications in personalized medicine. Mass spectra obtained using organic matrices revealed interference from matrix peaks overlapping with analyte peaks. The coefficient of determination (R2) was 0.9806 for CPT-11 and 0.9932 for SN-38, indicating strong linearity suitable for quantification. Moreover, the method achieved a lower limit of detection (LOD) of 62.76 ng/mL for CPT-11 and 189.87 ng/mL for SN-38, significantly enhancing the detection sensitivity by approximately 2-8 times compared with previous matrix-assisted laser desorption/ionization (MALDI) methodologies. This method was subsequently applied to the quantitative determination of analytes in mouse serum. The analyte recoveries for CPT-11 and SN-38 were 95.40% and 92.95%, respectively. Overall, this study offers potential insights and opens avenues for developing new nanomaterials as a MALDI nanomatrix, demonstrating enhanced capabilities for the rapid, specific, and sensitive detection of small biomolecules within the realms of analytical chemistry and personalized medicine.
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Affiliation(s)
- Govinda Mandal
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Muhammad Umar
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Rui Lv
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, Jiangsu, China.
| | - Ruochen Guo
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Tianjin Ge
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Muhammad Awais
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Shunli Yang
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Muhammad Sajjad Ul Hasan
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, Jiangsu, China
| | - Jian Liu
- Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, Jiangsu, China.
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Xu S, Lan H, Huang C, Ge X, Zhu J. Mechanisms and emerging strategies for irinotecan-induced diarrhea. Eur J Pharmacol 2024; 974:176614. [PMID: 38677535 DOI: 10.1016/j.ejphar.2024.176614] [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: 12/13/2023] [Revised: 04/24/2024] [Accepted: 04/24/2024] [Indexed: 04/29/2024]
Abstract
Irinotecan (also known as CPT-11) is a topoisomerase I inhibitor first approved for clinical use as an anticancer agent in 1996. Over the past more than two decades, it has been widely used for combination regimens to treat various malignancies, especially in gastrointestinal and lung cancers. However, severe dose-limiting toxicities, especially gastrointestinal toxicity such as late-onset diarrhea, were frequently observed in irinotecan-based therapy, thus largely limiting the clinical application of this agent. Current knowledge regarding the pathogenesis of irinotecan-induced diarrhea is characterized by the complicated metabolism of irinotecan to its active metabolite SN-38 and inactive metabolite SN-38G. A series of enzymes and transporters were involved in these metabolic processes, including UGT1A1 and CYP3A4. Genetic polymorphisms of these metabolizing enzymes were significantly associated with the occurrence of irinotecan-induced diarrhea. Recent discoveries and progress made on the detailed mechanisms enable the identification of potential biomarkers for predicting diarrhea and as such guiding the proper patient selection with a better range of tolerant dosages. In this review, we introduce the metabolic process of irinotecan and describe the pathogenic mechanisms underlying irinotecan-induced diarrhea. Based on the mechanisms, we further outline the potential biomarkers for predicting the severity of diarrhea. Finally, based on the current experimental evidence in preclinical and clinical studies, we discuss and prospect the current and emerging strategies for the prevention of irinotecan-induced diarrhea.
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Affiliation(s)
- Shengkun Xu
- Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang 310022, China
| | - Huiyin Lan
- Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang 310022, China
| | - Chengyi Huang
- Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang 310022, China
| | - Xingnan Ge
- Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang 310022, China
| | - Ji Zhu
- Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang 310022, China.
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Hu DG, Marri S, Hulin JA, McKinnon RA, Mackenzie PI, Meech R. A Comprehensive Bioinformatic Analysis of RNA-seq Datasets Reveals a Differential and Variable Expression of Wildtype and Variant UGT1A Transcripts in Human Tissues and Their Deregulation in Cancers. Cancers (Basel) 2024; 16:353. [PMID: 38254842 PMCID: PMC10814044 DOI: 10.3390/cancers16020353] [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: 12/19/2023] [Revised: 01/05/2024] [Accepted: 01/11/2024] [Indexed: 01/24/2024] Open
Abstract
The UGT1A locus generates over 60 different alternatively spliced transcripts and 30 circular RNAs. To date, v2 and v3 transcripts are the only variant UGT1A transcripts that have been functionally characterized. Both v2 and v3 transcripts encode the same inactive variant UGT1A proteins (i2s) that can negatively regulate glucuronidation activity and influence cancer cell metabolism. However, the abundance and interindividual variability in the expression of v2 and v3 transcripts in human tissues and their potential deregulation in cancers have not been comprehensively assessed. To address this knowledge gap, we quantified the expression levels of v1, v2, and v3 transcripts using RNA-seq datasets with large cohorts of normal tissues and paired normal and tumor tissues from patients with six different cancer types (liver, kidney, colon, stomach, esophagus, and bladder cancer). We found that v2 and v3 abundance varied significantly between different tissue types, and that interindividual variation was also high within the same tissue type. Moreover, the ratio of v2 to v3 variants varied between tissues, implying their differential regulation. Our results showed higher v2 abundance in gastrointestinal tissues than liver and kidney tissues, suggesting a more significant negative regulation of glucuronidation by i2 proteins in gastrointestinal tissues than in liver and kidney tissues. We further showed differential deregulation of wildtype (v1) and variant transcripts (v2, v3) in cancers that generally increased the v2/v1 and/or v3/v1 expression ratios in tumors compared to normal tissues, indicating a more significant role of the variants in tumors. Finally, we report ten novel UGT1A transcripts with novel 3' terminal exons, most of which encode variant proteins with a similar structure to UGT1A_i2 proteins. These findings further emphasize the diversity of the UGT1A transcriptome and proteome.
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Affiliation(s)
- Dong Gui Hu
- College of Medicine and Public Health, Flinders Health and Medical Research Institute, Flinders University, Bedford Park, Adelaide 5042, Australia; (S.M.); (J.-A.H.); (R.A.M.); (P.I.M.); (R.M.)
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Basso J, Schwartsmann G, Ibaldi MR, Schaefer VD, Pavei CC, Hahn RZ, Antunes MV, Linden R. Evaluation of UGT1A1 and CYP3A Genotyping and Single-Point Irinotecan and Metabolite Concentrations as Predictors of the Occurrence of Adverse Events in Cancer Treatment. J Gastrointest Cancer 2023; 54:589-599. [PMID: 35710870 DOI: 10.1007/s12029-022-00840-0] [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] [Accepted: 06/05/2022] [Indexed: 10/18/2022]
Abstract
PURPOSE The variability on irinotecan (IRI) pharmacokinetics and toxicity has been attributed mostly to genetic variations in the UGT1A1 gene, responsible for conjugation of the active metabolite SN-38. Also, CYP3A mediates the formation of inactive oxidative metabolites of IRI. The association between the occurrence of severe adverse events, pharmacokinetics parameters, and UGT1A1 and CYP3A4 predicted phenotypes was evaluated, as the evaluation of [SN-38]/IRI dose ratio as predictor of severe adverse events. METHODS Forty-one patients undergoing IRI therapy were enrolled in the study. Blood samples were collected 15 min after the end of drug the infusion, for IRI, SN-38, SN-38G, bilirubin concentrations measurements, and UGT1A1 and CYP3A genotype estimation. Data on adverse event was reported. RESULTS Fifteen patients (36.5%) developed grade 3/4 adverse events. A total of 9.8% (n = 4) of the patients had UGT1A1 reduced activity phenotype, and 48.7% (n = 20) had UGT1A1 and 63.4% (n = 26) CYP3A intermediary phenotypes. Severe neutropenia and diarrhea were more prevalent in patients with reduced UGT1A1 in comparison with functional metabolism (50% and 75% versus 0% and 13%, respectively). SN-38 levels and its concentrations adjusted by IRI dose were significantly correlated to toxicity (rs = 0.31 (p = 0.05) and rs = 0.425 (p < 0.01)). The [SN-38]/IRI dose ratio had a ROC curve of 0.823 (95% CI 0.69-0.956) to detect any severe adverse event and 0.833 (95% CI 0.694-0.973) to detect severe diarrhea. The cut-off of 0.075 ng mL-1 mg-1 had 100% sensitivity and 65.7% specificity to predict severe diarrhea. CONCLUSION Our data confirmed the relevance of the pre-emptive genotypic information of UGT1A1. The [SN-38]/IRI ratio, measured 15 min after the end of the IRI infusion, was a strong predictor of severe toxicity and could be applied to minimize the burden of patients after IRI administration.
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Affiliation(s)
- Jeziel Basso
- Universidade Federal Do Rio Grande Do Sul, UFRGS, Postgraduate program, Porto Alegre, Brazil
| | - Gilberto Schwartsmann
- Universidade Federal Do Rio Grande Do Sul, UFRGS, Postgraduate program, Porto Alegre, Brazil
| | | | - Vitoria Daniela Schaefer
- Analytical Toxicology Laboratory, Universidade Feevale, Novo Hamburgo, RS, Brazil
- Graduate Program On Toxicology and Analytical Toxicology, Universidade Feevale, Novo Hamburgo, RS, Brazil
| | - Carla Casagrande Pavei
- Medical Residency in Oncology of Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil
| | - Roberta Zilles Hahn
- Analytical Toxicology Laboratory, Universidade Feevale, Novo Hamburgo, RS, Brazil
| | - Marina Venzon Antunes
- Analytical Toxicology Laboratory, Universidade Feevale, Novo Hamburgo, RS, Brazil
- Graduate Program On Toxicology and Analytical Toxicology, Universidade Feevale, Novo Hamburgo, RS, Brazil
| | - Rafael Linden
- Analytical Toxicology Laboratory, Universidade Feevale, Novo Hamburgo, RS, Brazil.
- Graduate Program On Toxicology and Analytical Toxicology, Universidade Feevale, Novo Hamburgo, RS, Brazil.
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Aoullay Z, Smith A, Slaoui M, El Bouchikhi I, Ghazal H, Al Idrissi N, Meddah B, Lynch KL, Cherrah Y, Wu AHB. Predictive Value of ABCC2 and UGT1A1 Polymorphisms on Irinotecan-Related Toxicities in Patients with Cancer. Genet Test Mol Biomarkers 2023; 27:133-141. [PMID: 37257181 DOI: 10.1089/gtmb.2022.0109] [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: 06/02/2023] Open
Abstract
Background: There is extensive interindividual variability in response and tolerance to anticancer drugs. This heterogeneity provides a major limitation to the "rational" use of cytotoxic drugs, and it becomes a major problem in oncology giving a narrow therapeutic window with a vital risk. Among these anticancer drugs, irinotecan can cause dose-limiting toxicities, commonly diarrhea and neutropenia. Interaction among pathways of activation/inactivation (UGT1A1) and hepatobiliary transport of irinotecan and its metabolites could, in part, explain its interindividual variability. The objective of this study was to perform an exploratory analysis to evaluate the correlation between the genetic polymorphisms of UGT1A1 and ABCC2 with the different toxicities associated with irinotecan treatment. Materials and Methods: Seventy-five patients with solid cancers were included, all were administered an irinotecan-based regimen in both Mission Bay Medical Center; and Zuckerberg San Francisco General Hospital from May 2016 to December 2016. The patients' genotyping was performed for both the UGT1A1*28 polymorphism, and the ABCC2 - 1549G>A, and ABCC2 - 1249G>A single nucleotide polymorphism. Comparisons among qualitative data were assessed using the χ2-test, and Fisher's exact test in the case of small group sizes. Results: Diarrhea was observed in 40 patients (53.3%), among them only 9 patients had high grades diarrhea (grades III and IV). Grades III/IV of nausea were more frequently associated with the ABCC2-1549 AA genotype (83.3% p = 0.004) in patients with colorectal cancer. In pancreatic cancer, a significant absence of diarrhea grades III-IV was noted in patients with the ABCC2 1249 GG genotype compared to the other ABCC2 1249 genotypes.
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Affiliation(s)
- Zineb Aoullay
- Department of Sciences du Médicament, Laboratory of Pharmacology and Toxicology, Faculty of Medicine and Pharmacy of Rabat, University Mohamed V Rabat, Rabat, Morocco
- Department of Laboratory Medicine, University of California San Francisco and Zuckerberg San Francisco General Hospital, San Francisco, California, USA
- Institut de Recherche sur le Cancer-IRC, Fes, Morocco
| | - Andrew Smith
- Department of Laboratory Medicine, University of California San Francisco and Zuckerberg San Francisco General Hospital, San Francisco, California, USA
| | - Meriem Slaoui
- Research Team in Tumour Pathology, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Morocco
| | - Ihssane El Bouchikhi
- Medical Genetics and Oncogenetics Laboratory, Hassan II University Hospital, Fez, Morocco
- Multidisciplanary Laboratory for Research & Innovation, GBG Department, Polydisciplinary Faculty of Khouribga, Sultan Moulay Slimane University, Khouribga, Morocco
| | - Hassan Ghazal
- Department of Fundamental Sciences, School of Medicine, Mohammed VI University of Health Sciences, Casablanca, Morocco
- National Center for Scientific and Technical Research, Rabat, Morocco
| | - Najib Al Idrissi
- Department of Surgery, School of Medicine, Mohammed VI University of Health Sciences, Casablanca, Morocco
| | - Bouchra Meddah
- Department of Sciences du Médicament, Laboratory of Pharmacology and Toxicology, Faculty of Medicine and Pharmacy of Rabat, University Mohamed V Rabat, Rabat, Morocco
| | - Kara L Lynch
- Department of Laboratory Medicine, University of California San Francisco and Zuckerberg San Francisco General Hospital, San Francisco, California, USA
| | - Yahia Cherrah
- Department of Sciences du Médicament, Laboratory of Pharmacology and Toxicology, Faculty of Medicine and Pharmacy of Rabat, University Mohamed V Rabat, Rabat, Morocco
| | - Alan H B Wu
- Department of Laboratory Medicine, University of California San Francisco and Zuckerberg San Francisco General Hospital, San Francisco, California, USA
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The Somatic Mutation Landscape of UDP-Glycosyltransferase ( UGT) Genes in Human Cancers. Cancers (Basel) 2022; 14:cancers14225708. [PMID: 36428799 PMCID: PMC9688768 DOI: 10.3390/cancers14225708] [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] [Received: 10/07/2022] [Revised: 11/16/2022] [Accepted: 11/18/2022] [Indexed: 11/23/2022] Open
Abstract
The human UDP-glycosyltransferase (UGTs) superfamily has a critical role in the metabolism of anticancer drugs and numerous pro/anti-cancer molecules (e.g., steroids, lipids, fatty acids, bile acids and carcinogens). Recent studies have shown wide and abundant expression of UGT genes in human cancers. However, the extent to which UGT genes acquire somatic mutations within tumors remains to be systematically investigated. In the present study, our comprehensive analysis of the somatic mutation profiles of 10,069 tumors from 33 different TCGA cancer types identified 3427 somatic mutations in UGT genes. Overall, nearly 18% (1802/10,069) of the assessed tumors had mutations in UGT genes with huge variations in mutation frequency across different cancer types, ranging from over 25% in five cancers (COAD, LUAD, LUSC, SKCM and UCSC) to less than 5% in eight cancers (LAML, MESO, PCPG, PAAD, PRAD, TGCT, THYM and UVM). All 22 UGT genes showed somatic mutations in tumors, with UGT2B4, UGT3A1 and UGT3A2 showing the largest number of mutations (289, 307 and 255 mutations, respectively). Nearly 65% (2260/3427) of the mutations were missense, frame-shift and nonsense mutations that have been predicted to code for variant UGT proteins. Furthermore, about 10% (362/3427) of the mutations occurred in non-coding regions (5' UTR, 3' UTR and splice sites) that may be able to alter the efficiency of translation initiation, miRNA regulation or the splicing of UGT transcripts. In conclusion, our data show widespread somatic mutations of UGT genes in human cancers that may affect the capacity of cancer cells to metabolize anticancer drugs and endobiotics that control pro/anti-cancer signaling pathways. This highlights their potential utility as biomarkers for predicting therapeutic efficacy and clinical outcomes.
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Elz AS, Trevaskis NL, Porter CJH, Bowen JM, Prestidge CA. Smart design approaches for orally administered lipophilic prodrugs to promote lymphatic transport. J Control Release 2021; 341:676-701. [PMID: 34896450 DOI: 10.1016/j.jconrel.2021.12.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/03/2021] [Accepted: 12/04/2021] [Indexed: 12/22/2022]
Abstract
Challenges to effective delivery of drugs following oral administration has attracted growing interest over recent decades. Small molecule drugs (<1000 Da) are generally absorbed across the gastrointestinal tract into the portal blood and further transported to the systemic circulation via the liver. This can result in a significant reduction to the oral bioavailability of drugs that are metabolically labile and ultimately lead to ineffective exposure and treatment. Targeting drug delivery to the intestinal lymphatics is attracting increased attention as an alternative route of drug transportation providing multiple benefits. These include bypassing hepatic first-pass metabolism and selectively targeting disease reservoirs residing within the lymphatic system. The particular physicochemical requirements for drugs to be able to access the lymphatics after oral delivery include high lipophilicity (logP>5) and high long-chain triglyceride solubility (> 50 mg/g), properties required to enable drug association with the lipoprotein transport pathway. The majority of small molecule drugs, however, are not this lipophilic and therefore not substantially transported via the intestinal lymph. This has contributed to a growing body of investigation into prodrug approaches to deliver drugs to the lymphatic system by chemical manipulation. Optimised lipophilic prodrugs have the potential to increase lymphatic transport thereby improving oral pharmacokinetics via a reduction in first pass metabolism and may also target of disease-specific reservoirs within the lymphatics. This may provide advantages for current pharmacotherapy approaches for a wide array of pathological conditions, e.g. immune disease, cancer and metabolic disease, and also presents a promising approach for advanced vaccination strategies. In this review, specific emphasis is placed on medicinal chemistry strategies that have been successfully employed to design lipophilic prodrugs to deliberately enable lymphatic transport. Recent progress and opportunities in medicinal chemistry and drug delivery that enable new platforms for efficacious and safe delivery of drugs are critically evaluated.
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Affiliation(s)
- Aurelia S Elz
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia.
| | - Natalie L Trevaskis
- Department of Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC 3052, Australia.
| | - Christopher J H Porter
- Department of Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC 3052, Australia.
| | - Joanne M Bowen
- School of Biomedicine, The University of Adelaide, Adelaide, SA 5005, Australia.
| | - Clive A Prestidge
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia.
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Riera P, Páez D. Elucidating the role of pharmacogenetics in irinotecan efficacy and adverse events in metastatic colorectal cancer patients. Expert Opin Drug Metab Toxicol 2021; 17:1157-1163. [PMID: 34486919 DOI: 10.1080/17425255.2021.1974397] [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: 10/20/2022]
Abstract
INTRODUCTION Irinotecan is a cytotoxic agent that is widely used in the treatment of several types of solid tumors. However, although it is generally well tolerated, approximately 20% to 35% of patients develop severe toxicity, particularly delayed-type diarrhea and neutropenia. As the incidence of such toxicities is often associated with the UGT1A1 *28/*28, *6/*28 and *6/*6 genotypes, individualized dosing could reduce these adverse events. Furthermore, prospective trials have shown that patients harboring the UGT1A1 *1/*1 and *1/*28 genotypes can tolerate higher doses of irinotecan, which may in turn impact on a better outcome. Upfront UGT1A1 genotyping could therefore be a usefulness strategy in order to individualize irinotecan dosing, but consensus on the recommended dose based on the UGT1A1 genotype is still lacking. AREAS COVERED This review summarizes the results of the main pharmacogenetic studies focused on irinotecan. We provide an overview of current evidence and recommendations for individualized dosing of irinotecan in metastatic colorectal cancer patients. EXPERT OPINION Implementation of UGT1A1*28 and UGT1A1*6 genotyping in clinical practice is a first step toward personalizing irinotecan therapy. This approach is likely to improve patient care and reduce healthcare costs. Future large and prospective studies will help to clarify the clinical value of other genetic markers in irinotecan treatment personalization.
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Affiliation(s)
- Pau Riera
- Pharmacy Department, Hospital De La Santa Creu I Sant Pau, Barcelona, Spain.,U705, Isciii Center for Biomedical Research on Rare Diseases (Ciberer), Barcelona, Spain
| | - David Páez
- U705, Isciii Center for Biomedical Research on Rare Diseases (Ciberer), Barcelona, Spain.,Medical Oncology Department, Hospital De La Santa Creu I Sant Pau, Barcelona, Spain
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Liu Z, Martin JH, Liauw W, McLachlan SA, Link E, Matera A, Thompson M, Jefford M, Hicks RJ, Cullinane C, Hatzimihalis A, Campbell I, Crowley S, Beale PJ, Karapetis CS, Price T, Burge ME, Michael M. Evaluation of pharmacogenomics and hepatic nuclear imaging-related covariates by population pharmacokinetic models of irinotecan and its metabolites. Eur J Clin Pharmacol 2021; 78:53-64. [PMID: 34480602 DOI: 10.1007/s00228-021-03206-w] [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: 04/14/2021] [Accepted: 08/13/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Body surface area (BSA)-based dosing of irinotecan (IR) does not account for its pharmacokinetic (PK) and pharmacodynamic (PD) variabilities. Functional hepatic nuclear imaging (HNI) and excretory/metabolic/PD pharmacogenomics have shown correlations with IR disposition and toxicity/efficacy. This study reports the development of a nonlinear mixed-effect population model to identify pharmacogenomic and HNI-related covariates that impact on IR disposition to support dosage optimization. METHODS Patients had advanced colorectal cancer treated with IR combination therapy. Baseline blood was analysed by Affymetrix DMET™ Plus Array and, for PD, single nucleotide polymorphisms (SNPs) by Sanger sequencing. For HNI, patients underwent 99mTc-IDA hepatic imaging, and data was analysed for hepatic extraction/excretion parameters. Blood was taken for IR and metabolite (SN38, SN38G) analysis on day 1 cycle 1. Population modelling utilised NONMEM version 7.2.0, with structural PK models developed for each moiety. Covariates include patient demographics, HNI parameters and pharmacogenomic variants. RESULTS Analysis included (i) PK data: 32 patients; (ii) pharmacogenomic data: 31 patients: 750 DMET and 22 PD variants; and (iii) HNI data: 32 patients. On initial analysis, overall five SNPs were identified as significant covariates for CLSN38. Only UGT1A3_c.31 T > C and ABCB1_c.3435C > T were included in the final model, whereby CLSN38 reduced from 76.8 to 55.1%. CONCLUSION The identified UGT1A3_c.31 T > C and ABCB1_c.3435C > T variants, from wild type to homozygous, were included in the final model for SN38 clearance.
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Affiliation(s)
- Zheng Liu
- School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, Australia.,Clinical Pharmacology, Department of Medicine, The Royal Children's Hospital Melbourne, Melbourne, Australia.,Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | - Jennifer H Martin
- School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, Australia
| | - Winston Liauw
- Department of Medical Oncology, St. George's Hospital, Sydney, Australia
| | - Sue-Anne McLachlan
- Department of Medical Oncology, St. Vincent's Hospital, Melbourne, Australia
| | - Emma Link
- Biostatistics and Clinical Trials Centre, Peter MacCallum Cancer Centre, Melbourne, Australia.,Department of Oncology, Sir Peter MacCallum, University of Melbourne, Melbourne, Australia
| | - Anetta Matera
- Biostatistics and Clinical Trials Centre, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Michael Thompson
- Department of Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Michael Jefford
- Department of Oncology, Sir Peter MacCallum, University of Melbourne, Melbourne, Australia.,Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia
| | - Rod J Hicks
- Department of Oncology, Sir Peter MacCallum, University of Melbourne, Melbourne, Australia.,Department of Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Carleen Cullinane
- Department of Oncology, Sir Peter MacCallum, University of Melbourne, Melbourne, Australia.,Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Athena Hatzimihalis
- Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Ian Campbell
- Department of Oncology, Sir Peter MacCallum, University of Melbourne, Melbourne, Australia.,Victorian Breast Cancer Research Cooperative (VBCRC) Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Simone Crowley
- Previously Victorian Breast Cancer Research Cooperative (VBCRC) Cancer Genetics Laboratory, The Murdoch Children's Research Institute, The Royal Children's Hospital, Peter MacCallum Cancer Centre), MelbourneMelbourne, Australia
| | - Phillip J Beale
- Department of Medical Oncology, Concord and Royal Prince Alfred Hospital, Sydney, Australia
| | - Christos S Karapetis
- Department of Medical Oncology, Flinders Medical Centre, Flinders Centre for Innovation in Cancer, Adelaide, Australia
| | - Timothy Price
- Department of Medical Oncology, The Queen Elizabeth Hospital, Adelaide, Australia
| | - Mathew E Burge
- Department of Medical Oncology, Royal Brisbane and Women's Hospital, Brisbane, Australia
| | - Michael Michael
- Department of Oncology, Sir Peter MacCallum, University of Melbourne, Melbourne, Australia. .,Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia.
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11
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Anderson JT, Huang KM, Lustberg MB, Sparreboom A, Hu S. Solute Carrier Transportome in Chemotherapy-Induced Adverse Drug Reactions. Rev Physiol Biochem Pharmacol 2020; 183:177-215. [PMID: 32761456 DOI: 10.1007/112_2020_30] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Members of the solute carrier (SLC) family of transporters are responsible for the cellular influx of a broad range of endogenous compounds and xenobiotics. These proteins are highly expressed in the gastrointestinal tract and eliminating organs such as the liver and kidney, and are considered to be of particular importance in governing drug absorption and elimination. Many of the same transporters are also expressed in a wide variety of organs targeted by clinically important anticancer drugs, directly affect cellular sensitivity to these agents, and indirectly influence treatment-related side effects. Furthermore, targeted intervention strategies involving the use of transport inhibitors have been recently developed, and have provided promising lead candidates for combinatorial therapies associated with decreased toxicity. Gaining a better understanding of the complex interplay between transporter-mediated on-target and off-target drug disposition will help guide the further development of these novel treatment strategies to prevent drug accumulation in toxicity-associated organs, and improve the safety of currently available treatment modalities. In this report, we provide an update on this rapidly emerging field with particular emphasis on anticancer drugs belonging to the classes of taxanes, platinum derivatives, nucleoside analogs, and anthracyclines.
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Affiliation(s)
- Jason T Anderson
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Kevin M Huang
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Maryam B Lustberg
- Department of Medical Oncology, The Ohio State University, Comprehensive Cancer Center, Columbus, OH, USA
| | - Alex Sparreboom
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Shuiying Hu
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
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12
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Gao WF, Li YX, Zhang WH, Tao R, Yin TT, Wang YJ, Liu LN, Fu ZW, Li SN, Liu NR, Zhang H, Liu G, Zhao LZ, Zhang XP, Zhang CZ. Comparison of the inhibition potential of parthenolide and micheliolide on various UDP-glucuronosyltransferase isoforms. Xenobiotica 2019; 49:1158-1163. [PMID: 30484368 DOI: 10.1080/00498254.2018.1544383] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 10/31/2018] [Accepted: 11/01/2018] [Indexed: 10/27/2022]
Abstract
Parthenolide (PTL) and micheliolide (MCL) are sesquiterpene lactones with similar structures, and both of them have been reported to exhibit multiple biochemical and pharmacological activities. This study aims to investigate the inhibition of these two compounds on the activity of UDP-glucuronosyltransferases (UGTs). In vitro incubation mixture for recombinant UGTs-catalyzed glucuronidation metabolism of 4-methylumbelliferone (4-MU) was utilized to investigate the inhibition potential. Inhibition kinetics (including inhibition type and parameters) were determined, and in silico docking was employed to elucidate the inhibition difference between PTL and MCL on UGT1A1. MCL showed no inhibition toward all the UGT isoforms, and PTL showed strong inhibition toward UGT1A1. The half-maximal inhibitory concentration (IC50) of PTL on the activity of UGT1A1 was determined to be 64.4 μM. Inhibition kinetics determination showed that PTL exerted noncompetitive inhibition toward UGT1A1, and the inhibition kinetic constant (Ki) was determined to be 12.1 μM. In silico docking method has been employed to show that hydrogen bonds between PTL and the activity cavity of UGT1A1 contributed to the stronger inhibition of PTL on the activity of UGT1A1 than MCL. In conclusion, PTL can more easily induce drug-drug interaction (DDI) with clinical drugs mainly undergoing UGT1A1-catalyzed glucuronidation.
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Affiliation(s)
- Wei-Feng Gao
- a Department of Colorectal Surgery , Tianjin Union Medical Center , Tianjin , China
| | - Yi-Xuan Li
- a Department of Colorectal Surgery , Tianjin Union Medical Center , Tianjin , China
- b Department of Clinical Science of Integrated TCM and Western Medicine , Tianjin University of Traditional Chinese Medicine , Tianjin , China
| | - Wei-Hua Zhang
- a Department of Colorectal Surgery , Tianjin Union Medical Center , Tianjin , China
| | - Ran Tao
- c Basic Medical College, Hebei North University , Hebei , China
| | - Ting-Ting Yin
- b Department of Clinical Science of Integrated TCM and Western Medicine , Tianjin University of Traditional Chinese Medicine , Tianjin , China
| | - Yi-Jia Wang
- d Department of Pathology , Tianjin Union Medical Center , Tianjin , China
| | - Li-Na Liu
- a Department of Colorectal Surgery , Tianjin Union Medical Center , Tianjin , China
| | - Zhi-Wei Fu
- e Department of Toxicology School of Public Health , Tianjin Medical University , Tianjin , China
| | - Sai-Nan Li
- e Department of Toxicology School of Public Health , Tianjin Medical University , Tianjin , China
| | - Nai-Rong Liu
- e Department of Toxicology School of Public Health , Tianjin Medical University , Tianjin , China
| | - Heng Zhang
- f Tianjin Union Medical Center , Tianjin , China
| | - Guang Liu
- f Tianjin Union Medical Center , Tianjin , China
| | - Li-Zhong Zhao
- a Department of Colorectal Surgery , Tianjin Union Medical Center , Tianjin , China
| | - Xi-Peng Zhang
- a Department of Colorectal Surgery , Tianjin Union Medical Center , Tianjin , China
| | - Chun-Ze Zhang
- a Department of Colorectal Surgery , Tianjin Union Medical Center , Tianjin , China
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13
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Hahn RZ, Antunes MV, Verza SG, Perassolo MS, Suyenaga ES, Schwartsmann G, Linden R. Pharmacokinetic and Pharmacogenetic Markers of Irinotecan Toxicity. Curr Med Chem 2019; 26:2085-2107. [PMID: 29932028 DOI: 10.2174/0929867325666180622141101] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2017] [Revised: 06/04/2018] [Accepted: 06/06/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND Irinotecan (IRI) is a widely used chemotherapeutic drug, mostly used for first-line treatment of colorectal and pancreatic cancer. IRI doses are usually established based on patient's body surface area, an approach associated with large inter-individual variability in drug exposure and high incidence of severe toxicity. Toxic and therapeutic effects of IRI are also due to its active metabolite SN-38, reported to be up to 100 times more cytotoxic than IRI. SN-38 is detoxified by the formation of SN-38 glucuronide, through UGT1A1. Genetic polymorphisms in the UGT1A1 gene are associated to higher exposures to SN-38 and severe toxicity. Pharmacokinetic models to describe IRI and SN-38 kinetic profiles are available, with few studies exploring pharmacokinetic and pharmacogenetic-based dose individualization. The aim of this manuscript is to review the available evidence supporting pharmacogenetic and pharmacokinetic dose individualization of IRI in order to reduce the occurrence of severe toxicity during cancer treatment. METHODS The PubMed database was searched, considering papers published in the period from 1995-2017, using the keywords irinotecan, pharmacogenetics, metabolic genotyping, dose individualization, therapeutic drug monitoring, pharmacokinetics and pharmacodynamics, either alone or in combination, with original papers being selected based on the presence of relevant data. CONCLUSION The findings of this review confirm the importance of considering individual patient characteristics to select IRI doses. Currently, the most straightforward approach for IRI dose individualization is UGT1A1 genotyping. However, this strategy is sub-optimal due to several other genetic and environmental contributions to the variable pharmacokinetics of IRI and its active metabolite. The use of dried blood spot sampling could allow the clinical application of limited sampling and population pharmacokinetic models for IRI doses individualization.
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Affiliation(s)
- Roberta Zilles Hahn
- Laboratory of Analytical Toxicology, Institute of Health Sciences, Universidade Feevale, Novo Hamburgo- RS, Brazil.,Graduate Program on Toxicology and Analytical Toxicology, Universidade Feevale, Novo Hamburgo- RS, Brazil
| | - Marina Venzon Antunes
- Laboratory of Analytical Toxicology, Institute of Health Sciences, Universidade Feevale, Novo Hamburgo- RS, Brazil.,Graduate Program on Toxicology and Analytical Toxicology, Universidade Feevale, Novo Hamburgo- RS, Brazil
| | - Simone Gasparin Verza
- Graduate Program on Toxicology and Analytical Toxicology, Universidade Feevale, Novo Hamburgo- RS, Brazil
| | - Magda Susana Perassolo
- Graduate Program on Toxicology and Analytical Toxicology, Universidade Feevale, Novo Hamburgo- RS, Brazil
| | - Edna Sayuri Suyenaga
- Graduate Program on Toxicology and Analytical Toxicology, Universidade Feevale, Novo Hamburgo- RS, Brazil
| | | | - Rafael Linden
- Laboratory of Analytical Toxicology, Institute of Health Sciences, Universidade Feevale, Novo Hamburgo- RS, Brazil.,Graduate Program on Toxicology and Analytical Toxicology, Universidade Feevale, Novo Hamburgo- RS, Brazil
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14
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Gao Y, Li W, Chen J, Wang X, Lv Y, Huang Y, Zhang Z, Xu F. Pharmacometabolomic prediction of individual differences of gastrointestinal toxicity complicating myelosuppression in rats induced by irinotecan. Acta Pharm Sin B 2019; 9:157-166. [PMID: 30766787 PMCID: PMC6362258 DOI: 10.1016/j.apsb.2018.09.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 08/21/2018] [Accepted: 08/30/2018] [Indexed: 12/13/2022] Open
Abstract
Pharmacometabolomics has been already successfully used in toxicity prediction for one specific adverse effect. However in clinical practice, two or more different toxicities are always accompanied with each other, which puts forward new challenges for pharmacometabolomics. Gastrointestinal toxicity and myelosuppression are two major adverse effects induced by Irinotecan (CPT-11), and often show large individual differences. In the current study, a pharmacometabolomic study was performed to screen the exclusive biomarkers in predose serums which could predict late-onset diarrhea and myelosuppression of CPT-11 simultaneously. The severity and sensitivity differences in gastrointestinal toxicity and myelosuppression were judged by delayed-onset diarrhea symptoms, histopathology examination, relative cytokines and blood cell counts. Mass spectrometry-based non-targeted and targeted metabolomics were conducted in sequence to dissect metabolite signatures in predose serums. Eventually, two groups of metabolites were screened out as predictors for individual differences in late-onset diarrhea and myelosuppression using binary logistic regression, respectively. This result was compared with existing predictors and validated by another independent external validation set. Our study indicates the prediction of toxicity could be possible upon predose metabolic profile. Pharmacometabolomics can be a potentially useful tool for complicating toxicity prediction. Our findings also provide a new insight into CPT-11 precision medicine.
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Key Words
- AUC-ROC, area under receiver operating characteristic
- BHB, β-hydroxybutyric acid
- Biomarkers
- C, control group
- CA, cholic acid
- CPT-11, irinotecan
- Complicating toxicity
- DBIL, direct bilirubin
- DCA, deoxycholic acid
- Diarrhea
- FDR, false discovery rate
- GCA, glycocholic acid
- Gastrointestinal toxicity
- IBIL, indirect bilirubin
- IT-TOF/MS, ion trap/time-offlight hybrid mass spectrometry
- Individual differences
- Irinotecan
- Lys, lysine
- MSTFA, N-methyl-N-trifluoroacetamide
- Metabolomics
- NS, non-sensitive group
- NSgt, non-sensitive for gastrointestinal toxicity
- NSmt, non-sensitive for myelosuppression toxicity
- OPLS-DA, orthogonal partial least-squares-discriminant analysis
- PCA, principal component analysis
- PLS-DA, partial least-squares-discriminant analysis
- Phe, phenylalanine
- Prediction
- QC, quality control
- RSD, relative standard deviation
- S, sensitive group
- Sgt, sensitive for gastrointestinal toxicity
- Smt, sensitive for myelosuppression toxicity
- T, CPT-11 treated group
- Trp, tryptophan
- UFLC, ultrafast liquid chromatography
- VIP, variable importance in the projection
- pFDR, false-discovery-rate-adjusted P value
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Affiliation(s)
- Yiqiao Gao
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, China
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Wei Li
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, China
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Jiaqing Chen
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, China
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Xu Wang
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, China
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Yingtong Lv
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, China
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Yin Huang
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, China
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Zunjian Zhang
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, China
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Fengguo Xu
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, China
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
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15
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Yang Y, Zhou M, Hu M, Cui Y, Zhong Q, Liang L, Huang F. UGT1A1*6 and UGT1A1*28 polymorphisms are correlated with irinotecan-induced toxicity: A meta-analysis. Asia Pac J Clin Oncol 2018; 14:e479-e489. [DOI: 10.1111/ajco.13028] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 05/20/2018] [Indexed: 02/06/2023]
Affiliation(s)
- Yuwei Yang
- Department of Epidemiology and Biostatistics; School of Public Health; Anhui Medical University; Hefei China
| | - MengMeng Zhou
- Department of Epidemiology and Biostatistics; School of Public Health; Anhui Medical University; Hefei China
| | - Mingjun Hu
- Department of Epidemiology and Biostatistics; School of Public Health; Anhui Medical University; Hefei China
| | - Yanjie Cui
- Department of Epidemiology and Biostatistics; School of Public Health; Anhui Medical University; Hefei China
| | - Qi Zhong
- Department of Epidemiology and Biostatistics; School of Public Health; Anhui Medical University; Hefei China
| | - Ling Liang
- Department of Epidemiology and Biostatistics; School of Public Health; Anhui Medical University; Hefei China
| | - Fen Huang
- Department of Epidemiology and Biostatistics; School of Public Health; Anhui Medical University; Hefei China
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16
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Rugo HS, Cortes J, Awada A, O'Shaughnessy J, Twelves C, Im SA, Hannah A, Lu L, Sy S, Caygill K, Zajchowski DA, Davis DW, Tagliaferri M, Hoch U, Perez EA. Change in Topoisomerase 1-Positive Circulating Tumor Cells Affects Overall Survival in Patients with Advanced Breast Cancer after Treatment with Etirinotecan Pegol. Clin Cancer Res 2018; 24:3348-3357. [PMID: 29618616 DOI: 10.1158/1078-0432.ccr-17-3059] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 01/10/2018] [Accepted: 03/26/2018] [Indexed: 11/16/2022]
Abstract
Purpose: Preplanned exploratory analyses were performed to identify biomarkers in circulating tumor cells (CTC) predictive of response to the topoisomerase 1 inhibitor etirinotecan pegol (EP).Experimental Design: The BEACON trial treated patients with metastatic breast cancer (MBC) with EP or treatment of physician's choice (TPC). Blood from 656 of 852 patients (77%) was processed with ApoStream to enrich for CTCs. A multiplex immunofluorescence assay measured expression of candidate response biomarkers [topoisomerase 1 (Top1), topoisomerase 2 (Top2), Ki67, RAD51, ABCG2, γH2AX, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)] in CTCs. Patients were classified as Top1 low (Top1Lo) or Top1 high (Top1Hi) based on median CTC Top1 expression. Correlation of CTC biomarker expression at baseline, cycle 2 day 1 (C2D1), and cycle 4 day 1 with overall survival (OS) was investigated using Cox regression and Kaplan-Meier analyses.Results: Overall, 98% of samples were successfully processed, of which 97% had detectable CTCs (median, 47-63 CTCs/mL; range, 0-2,020 CTCs/mL). Top1, Top2, and TUNEL expression was detected in 52% to 90% of samples; no significant associations with OS were observed in pretreatment samples for either group. EP-treated patients with low C2D1Top1+ CTCs had improved OS compared with those with higher positivity (14.1 months vs. 11.0 months, respectively; HR, 0.7; P = 0.02); this difference was not seen in TPC-treated patients (HR, 1.12; P = 0.48). Patients whose CTCs decreased from Top1Hi to Top1Lo at C2D1 had the greatest OS benefit from EP (HR, 0.57; P = 0.01).Conclusions: CTC Top1 expression following EP treatment may identify patients with MBC most likely to have an OS benefit. Clin Cancer Res; 24(14); 3348-57. ©2018 AACR.
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Affiliation(s)
- Hope S Rugo
- University of California, San Francisco, San Francisco, California
| | - Javier Cortes
- Ramon y Cajal University Hospital, Madrid, and Vall D'Hebron Institute of Oncology, Barcelona, Spain
| | - Ahmad Awada
- Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium
| | - Joyce O'Shaughnessy
- Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, Texas
| | - Chris Twelves
- University of Leeds and Leeds Teaching Hospital Trust, Leeds, United Kingdom
| | - Seock-Ah Im
- Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | | | - Lin Lu
- Nektar Therapeutics, San Francisco, California
| | - Sherwin Sy
- Nektar Therapeutics, San Francisco, California
| | | | | | | | | | - Ute Hoch
- Nektar Therapeutics, San Francisco, California.
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17
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Effect of UGT, SLCO, ABCB and ABCC polymorphisms on irinotecan toxicity. Med Clin (Barc) 2018; 151:425-430. [PMID: 29499902 DOI: 10.1016/j.medcli.2018.01.016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 01/15/2018] [Accepted: 01/18/2018] [Indexed: 02/03/2023]
Abstract
BACKGROUND AND OBJECTIVES Evaluate the relationship between the presence of polymorphisms in genes involved in the pharmacodynamics of irinotecan (UGT1A, SLCO1B1, ABCB1 and ABCC2) and the safety of irinotecan in the treatment of metastatic colorectal cancer (mCRC). PATIENTS AND METHODS Prospective observational, single-centre study of 30 months duration, which included patients diagnosed with mCRC treated with FOLFIRI was carried out. Toxicity was evaluated in each treatment cycle according to the Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 NCI. Genomic DNA was obtained with a peripheral blood sample from an extraction method based on alkaline lysis. Genetic characterisation was performed using the LigthCycler®480 platform and allele-specific HybProbe® fluorescent probes. Analysed polymorphisms were: UGT1A1*28, UGT1A1*60, UGT1A7*1,*2,*3,*4, UGT1A7*12, UGT1A9*22, SLCO1B1 (rs11045879), ABCC2 (rs717620) and ABCB1 (rs1045642). RESULTS Thirty-four patients were included (73.5% were male, mean age 59.9 years [27-81]) in the study. Polymorphisms rs8175347, rs17868323, rs3832043, rs11692021 and rs7577677 were associated with a higher incidence of adverse effects. Furthermore, it was observed that those patients with wild-type in UGT family genes analysed have lower rates of toxicity associated with irinotecan treatment than those with certain mutated allele (P=.010). CONCLUSIONS These results suggest that the presence of certain polymorphisms in the UGT1A family of genes is related to the development of toxicity during treatment with irinotecan.
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18
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Choi SS, Yoon K, Choi SA, Yoon SB, Kim SU, Lee HJ. Tumor-specific gene therapy for pancreatic cancer using human neural stem cells encoding carboxylesterase. Oncotarget 2018; 7:75319-75327. [PMID: 27659534 PMCID: PMC5342743 DOI: 10.18632/oncotarget.12173] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 09/13/2016] [Indexed: 01/14/2023] Open
Abstract
Advanced pancreatic cancer is one of the most lethal malignant human diseases lacking effective treatment. Its extremely low survival rate necessitates development of novel therapeutic approach. Human neural stem cells (NSCs) are known to have tumor-tropic effect. We genetically engineered them to express rabbit carboxyl esterase (F3.CE), which activates prodrug CPT-11(irinotecan) into potent metabolite SN-38. We found significant inhibition of the growth of BxPC3 human pancreatic cancer cell line in vitro by F3.CE in presence of CPT-11. Apoptosis was also markedly increased in BxPC3 cells treated with F3.CE and CPT-11. The ligand VEGF and receptor VEGF-1(Flt1) were identified to be the relevant tumor-tropic chemoattractant. We confirmed in vivo that in mice injected with BxPC3 on their skin, there was significant reduction of tumor size in those treated with both F3.CE and BxPC3 adjacent to the cancer mass. Administration of F3.CE in conjunction with CPT-11 could be a new possibility as an effective treatment regimen for patients suffering from advanced pancreatic cancer.
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Affiliation(s)
- Sung S Choi
- Biomedical Research Institute, Chung-Ang University College of Medicine, Seoul, Korea
| | - Kichul Yoon
- Biomedical Research Institute, Chung-Ang University College of Medicine, Seoul, Korea.,Seoul Adventist Hospital, Seoul, Korea.,Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Seon-A Choi
- Futuristic Animal Resource & Research Center (FARRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Korea
| | - Seung-Bin Yoon
- Futuristic Animal Resource & Research Center (FARRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Korea
| | - Seung U Kim
- Division of Neurology, Department of Medicine, UBC Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Hong J Lee
- Biomedical Research Institute, Chung-Ang University College of Medicine, Seoul, Korea
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19
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Hahn RZ, Arnhold PC, Andriguetti NB, Schneider A, Klück HM, dos Reis SL, Bastiani MF, Kael I, da Silva ACC, Schwartsmann G, Antunes MV, Linden R. Determination of irinotecan and its metabolite SN-38 in dried blood spots using high-performance liquid-chromatography with fluorescence detection. J Pharm Biomed Anal 2018; 150:51-58. [DOI: 10.1016/j.jpba.2017.11.079] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Revised: 11/28/2017] [Accepted: 11/30/2017] [Indexed: 12/22/2022]
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20
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Abstract
DDAB (6,8-dichloro-9,9-dimethyl-7-oxo-7,9-dihydroacridin-2-yl benzoate) is a newly developed near-infrared fluorescent probe for human carboxylesterase 2 (hCE2), exhibiting high specificity and good reactivity for real-time monitoring the enzymatic activities of hCE2 in complex biological systems. In order to explore the applicability of DDAB in commonly used animal species, the interspecies difference in DDAB hydrolysis was carefully investigated by using liver microsomes from human and five experimental animals including mouse, rat, dog, minipig and monkey. Metabolite profiling demonstrated that DDAB hydrolysis could be catalyzed by all tested liver microsomes from different animals but displayed significant difference in the reaction rate. Chemical inhibition assays demonstrated that carboxylesterases (CEs) were the major enzymes involved in DDAB hydrolysis in all tested liver microsomes, indicating that DDAB was a selective substrate of CEs in a variety of mammals. However, the differential effects of loperamide (LPA, a specific inhibitor against hCE2) on DDAB hydrolysis among various species were observed. The apparent kinetic parameters and the maximum intrinsic clearances (CLmax) for DDAB hydrolysis in liver microsomes from different animals were determined, and the order of CLmax values for the formation of DDAO was CyLM>MLM≈PLM>RLM>HLM≈DLM. These findings were helpful for the rational use of DDAB as an imaging tool for CE2 in different mammals, as well as for translational researches on the function of mammalian CEs and CE2-associated drug-drug interactions.
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21
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Atasilp C, Chansriwong P, Sirachainan E, Reungwetwattana T, Puangpetch A, Prommas S, Sirilerttrakul S, Rerkarmnuaychoke B, Wongwaisayawan S, Sukasem C. Determination of irinotecan, SN-38 and SN-38 glucuronide using HPLC/MS/MS: Application in a clinical pharmacokinetic and personalized medicine in colorectal cancer patients. J Clin Lab Anal 2017; 32. [PMID: 28393405 DOI: 10.1002/jcla.22217] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Accepted: 02/27/2017] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND Irinotecan (CPT-11) is chemotherapy used mainly in the metastatic colorectal cancer. The purpose of this study was to develop and validate the LC-MS/MS for the simultaneous determination of CPT-11, SN-38, and SN-38G. METHODS A 100 μL of plasma was prepared after protein precipitation and analyzed on a C18 column using 0.1% acetic acid in water and 0.1% acetic acid in acetonitrile as mobile phases. The mass spectrometer worked with multiple reaction monitoring (MRM) in positive scan mode. The standard curves were linear on a concentration range of 5-10 000 ng/mL for CPT-11, 5-1000 ng/mL for SN-38, and 8-1000 ng/mL for SN-38G. RESULTS In this assay, the intra and interday precision consisted of ≤9.11% and ≤11.29% for CPT-11, ≤8.70% and 8.31% for SN-38, and ≤9.90 and 9.64% for SN-38G. CONCLUSION This method was successfully used to quantify CPT-11, SN-38, and SN-38G and applied to a pharmacokinetic study.
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Affiliation(s)
- Chalirmporn Atasilp
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.,Laboratory for Pharmacogenomics, Clinical Pathology, Somdetch Phra Debharatana Medical Centre, Ramathibodi Hospital, Bangkok, Thailand
| | - Pichai Chansriwong
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Ekapob Sirachainan
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Thanyanan Reungwetwattana
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Apichaya Puangpetch
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.,Laboratory for Pharmacogenomics, Clinical Pathology, Somdetch Phra Debharatana Medical Centre, Ramathibodi Hospital, Bangkok, Thailand
| | - Santirhat Prommas
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.,Laboratory for Pharmacogenomics, Clinical Pathology, Somdetch Phra Debharatana Medical Centre, Ramathibodi Hospital, Bangkok, Thailand
| | - Suwannee Sirilerttrakul
- Division of Medical Oncology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Budsaba Rerkarmnuaychoke
- Division of Human Genetics Laboratory, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Sansanee Wongwaisayawan
- Division of Anatomical Pathology, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Chonlaphat Sukasem
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.,Laboratory for Pharmacogenomics, Clinical Pathology, Somdetch Phra Debharatana Medical Centre, Ramathibodi Hospital, Bangkok, Thailand
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Virtual Clinical Studies to Examine the Probability Distribution of the AUC at Target Tissues Using Physiologically-Based Pharmacokinetic Modeling: Application to Analyses of the Effect of Genetic Polymorphism of Enzymes and Transporters on Irinotecan Induced Side Effects. Pharm Res 2017; 34:1584-1600. [PMID: 28397089 PMCID: PMC5498655 DOI: 10.1007/s11095-017-2153-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2016] [Accepted: 03/28/2017] [Indexed: 02/07/2023]
Abstract
Purpose To establish a physiologically-based pharmacokinetic (PBPK) model for analyzing the factors associated with side effects of irinotecan by using a computer-based virtual clinical study (VCS) because many controversial associations between various genetic polymorphisms and side effects of irinotecan have been reported. Methods To optimize biochemical parameters of irinotecan and its metabolites in the PBPK modeling, a Cluster Newton method was introduced. In the VCS, virtual patients were generated considering the inter-individual variability and genetic polymorphisms of enzymes and transporters. Results Approximately 30 sets of parameters of the PBPK model gave good reproduction of the pharmacokinetics of irinotecan and its metabolites. Of these, 19 sets gave relatively good description of the effect of UGT1A1 *28 and SLCO1B1 c.521T>C polymorphism on the SN-38 plasma concentration, neutropenia, and diarrhea observed in clinical studies reported mainly by Teft et al. (Br J Cancer. 112(5):857-65, 20). VCS also indicated that the frequency of significant association of biliary index with diarrhea was higher than that of UGT1A1 *28 polymorphism. Conclusion The VCS confirmed the importance of genetic polymorphisms of UGT1A1 *28 and SLCO1B1 c.521T>C in the irinotecan induced side effects. The VCS also indicated that biliary index is a better biomarker of diarrhea than UGT1A1 *28 polymorphism. Electronic supplementary material The online version of this article (doi:10.1007/s11095-017-2153-z) contains supplementary material, which is available to authorized users.
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Westphalen CB, Kruger S, Haas M, Heinemann V, Boeck S. Safety of palliative chemotherapy in advanced pancreatic cancer. Expert Opin Drug Saf 2016; 15:947-54. [PMID: 27070177 DOI: 10.1080/14740338.2016.1177510] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Pancreatic cancer is a major health burden. Currently, the majority of patients is diagnosed at advanced stages and thus qualifies for palliative chemotherapy. Gemcitabine monotherapy has been the gold standard for many years. Recently, more effective chemotherapeutic regimens have shown meaningful clinical activity in patients with metastatic pancreatic cancer. AREAS COVERED In this review we have aimed to give an overview on the treatment options for patients diagnosed with metastatic pancreatic cancer with an emphasis on the safety and toxicity of the applied regimens. We have conducted a pubmed search using the terms 'metastatic pancreatic cancer', 'palliative chemotherapy', 'safety' and 'toxicity'. Our special focus rested on randomized phase III trials to provide readers with the highest level of available evidence. EXPERT OPINION The emergence of new and more effective chemotherapy regimens gives clinicians more freedom in the treatment of metastatic pancreatic cancer. While being more effective, these regiments have a considerable degree of toxicity. Choosing the right treatment for any individual will be the next major challenge treating patients with pancreatic cancer.
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Affiliation(s)
- C Benedikt Westphalen
- a Department of Internal Medicine III and Comprehensive Cancer Center , Klinikum Grosshadern, Ludwig-Maximilians-University of Munich , Munich , Germany
| | - Stephan Kruger
- a Department of Internal Medicine III and Comprehensive Cancer Center , Klinikum Grosshadern, Ludwig-Maximilians-University of Munich , Munich , Germany
| | - Michael Haas
- a Department of Internal Medicine III and Comprehensive Cancer Center , Klinikum Grosshadern, Ludwig-Maximilians-University of Munich , Munich , Germany
| | - Volker Heinemann
- a Department of Internal Medicine III and Comprehensive Cancer Center , Klinikum Grosshadern, Ludwig-Maximilians-University of Munich , Munich , Germany
| | - Stefan Boeck
- a Department of Internal Medicine III and Comprehensive Cancer Center , Klinikum Grosshadern, Ludwig-Maximilians-University of Munich , Munich , Germany
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Wang W, Huang J, Tao Y, Lyu X, Yang L, Wu D, Tian Y. Phase II and UGT1A1 Polymorphism Study of Two Different Irinotecan Dosages Combined with Cisplatin as First-Line Therapy for Advanced Gastric Cancer. Chemotherapy 2016; 61:197-203. [PMID: 26872008 DOI: 10.1159/000442787] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 11/26/2015] [Indexed: 11/19/2022]
Abstract
BACKGROUND We investigated the efficacy and safety of biweekly irinotecan and cisplatin (IP) as first-line treatment in advanced gastric cancer patients. METHODS Irinotecan 125 mg/m2 on day 1 and cisplatin 60 mg/m2 on day 2 were administrated every 14 days. UGT1A1*28/*6 and toxicities were analyzed. RESULTS Forty-one eligible patients were enrolled. Fifteen patients, who were defined as the high-dose group, received starting doses of irinotecan 125 mg/m2. Twenty-six patients, who were defined as the low-dose group, received starting doses of irinotecan 80 mg/m2 and cisplatin 50 mg/m2. The response rate was 53.3% in the irinotecan high-dose group and 53.8% in the irinotecan low-dose group. The most common grade 3/4 toxicity was neutropenia (68.3%). No significant difference in grade 3/4 neutropenia was found between patients with the wild-type genotype and those with variant genotypes for UGT1A1*28 or UGT1A1*6. CONCLUSIONS The combination of biweekly irinotecan 80 mg/m2 and cisplatin 50 mg/m2 was active and tolerable. The role of the UGT1A1 genotype in clinical toxicity of an IP regimen requires further investigation.
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Xiao XG, Xia S, Zou M, Mei Q, Zhou L, Wang SJ, Chen Y. The relationship between UGT1A1 gene polymorphism and irinotecan effect on extensive-stage small-cell lung cancer. Onco Targets Ther 2015; 8:3575-83. [PMID: 26664141 PMCID: PMC4671801 DOI: 10.2147/ott.s95149] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Aims To analyze the distribution of uridine diphosphate glucuronosyltransferase (UGT)1A1 gene polymorphisms in Chinese patients with extensive-stage small-cell lung cancer (E-SCLC), and to evaluate correlations between the UGT1A1 gene polymorphisms and toxicity, and efficacy of irinotecan (CPT-11) based regimen in the patients with E-SCLC. Methods The study analyzed the distribution of UGT1A1*28/*6 gene polymorphisms by polymerase chain reaction amplification and pyrosequencing. The analysis of UGT1A1*28 and UGT1A1*6 gene polymorphisms was performed in 67 patients with E-SCLC admitted to the clinic in the Department of Oncology from June 2011 to January 2013. A total of 67 cases with E-SCLC treated with irinotecan (CPT-11)-based regimen were enrolled to observe the adverse events and efficacy during the chemotherapy, including objective response rate, progression-free survival (PFS) and overall survival (OS). The correlation between UGT1A1 gene polymorphisms and severe adverse events was analyzed. The influences of UGT1A1*6/*28 polymorphisms on objective response rate, PFS, and OS were also analyzed. Results The distribution of UGT1A1 genotypes among 67 patients was as follows: UGT1A1*28 wild-type (WT) genotype TA6/6 (56, 83.6%), heterozygous mutant genotype TA6/7 (11, 16.4%); UGT1A1*6 WT genotype G/G (45, 67.2%), heterozygous mutant genotype G/A (22, 32.8%); no significant difference of PFS and OS was observed between different genotypes. The incidence of grade 3 and 4 delayed diarrhea and neutropenia in the patients carrying UGT1A1*6 G/A mutation was higher than that in the WT genotype (36.4% vs 6.6% P=0.034; 27.2% vs 4.4% P=0.026, respectively). The incidence of grade 3 and 4 thrombocytopenia in the patients carrying UGT1A1*28 TA6/7 mutation was higher than that in the WT genotype (27.2% vs 1.8% P=0.017). The patients simultaneously carrying UGT1A1*28 TA6/7 and UGT1A1*6 G/A mutations were prone to suffering grade 3 and 4 delayed diarrhea and neutropenia. Conclusion For irinotecan-based regimens in E-SCLC, the UGT1A1*28 and UGT1A1*6 locus mutations can be regarded as predictors for severe adverse events. We also found that neither clinical response nor prognosis was significantly associated with the UGT1A1 gene polymorphisms.
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Affiliation(s)
- Xiao-Guang Xiao
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Shu Xia
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Man Zou
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Qi Mei
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Lei Zhou
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Shu-Jing Wang
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Yuan Chen
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
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Xiao X, Wang S, Xia S, Zou M, Li Y, Wei Y, Mei Q, Chen Y. Retrospective study of irinotecan/cisplatin followed by etoposide/cisplatin or the reverse sequence in extensive-stage small cell lung cancer. Onco Targets Ther 2015; 8:2209-14. [PMID: 26345293 PMCID: PMC4551306 DOI: 10.2147/ott.s89606] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Background Much research has confirmed the favorable effect of irinotecan/cisplatin (IP) and etoposide/cisplatin (EP) on extensive-stage small cell lung cancer (E-SCLC). This study investigated two sequential orders of IP and EP in the treatment of E-SCLC. We also compared the efficacy and safety of IP and EP in first-line chemotherapy in E-SCLC. Methods Ninety-three untreated patients with E-SCLC were randomly allocated to two groups. Group A received IP as first-line therapy until progression and then changed to EP; group B received EP as first-line therapy until tumor progression followed by IP. The primary endpoints were overall survival and time to second tumor progression. The secondary endpoints were first progression-free survival (PFS), ie, time from randomization to first occurrence of tumor progression after first-line treatment with IP or EP, tumor response, and safety of the different sequential treatment orders of IP and EP. Results Median overall survival was 15.4 months in group A (IP followed by EP) versus 15.7 months in group B (EP followed by IP; P=0.483). The median time to second tumor progression was 9.5 months in group A versus 9.9 months in group B (P=0.361). As first-line and second-line therapy, IP achieved a 95.9% and 60% disease control rate, respectively, and EP achieved 95.6% and 59% disease control rate. The median first PFS was not significantly different between group A and group B (6.5 months and 6.3 months, respectively; P=0.256). Grade 3/4 diarrhea appeared to be significantly more frequent with IP than with EP. The probability of anemia and thrombocytopenia was not significantly different between the two groups. However, significantly more patients who received the IP regimen as second-line treatment developed grade 3/4 neutropenia than those who received the IP regimen as first-line therapy. Conclusion There were no statistically significant differences in between the two sequences of IP and EP in the treatment of E-SCLC. Except EP regimen, IP may be another reserved regimen in the first-line treatment of E-SCLC.
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Affiliation(s)
- Xiaoguang Xiao
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Shujing Wang
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Shu Xia
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Man Zou
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Yang Li
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Yao Wei
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Qi Mei
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Yuan Chen
- Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
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Xiao D, Yang D, Guo L, Lu W, Charpentier M, Yan B. Regulation of carboxylesterase-2 expression by p53 family proteins and enhanced anti-cancer activities among 5-fluorouracil, irinotecan and doxazolidine prodrug. Br J Pharmacol 2015; 168:1989-99. [PMID: 23373735 DOI: 10.1111/bph.12125] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2012] [Revised: 11/05/2012] [Accepted: 12/10/2012] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND AND PURPOSE For four decades, 5-fluorouracil (5-FU) has been a major anti-cancer medicine. This drug is increasingly used with other anti-cancer agents such as irinotecan. Irinotecan and many others such as PPD (pentyl carbamate of p-aminobenzyl carbamate of doxazolidine) require activation by carboxylesterase-2 (CES2). 5-FU, on the other hand, reportedly induces CES2 in colorectal tumour lines. The aims of this study were to determine the molecular basis for the induction and to ascertain interactive cell-killing activity between 5-FU and ester prodrugs. EXPERIMENTAL APPROACH Colorectal and non-colorectal lines and xenografts were treated with 5-FU and the expression of CES2 was determined. Cell-killing activity of irinotecan and PPD were determined in the presence or absence of CES2 inhibitor. Several molecular experiments were used to determine the molecular basis for the induction. KEY RESULTS Without exceptions, robust induction was detected in cell lines expressing functional p53. High-level induction was also detected in xenografts. 5-FU pretreatment significantly increased cell-killing activity of irinotecan and PPD. Molecular experiments established that the induction was achieved by both transactivation and increased mRNA stability through p53. Either p63 or p73, functionally related to p53, did not support the transactivation. CONCLUSIONS AND IMPLICATIONS The results in this study suggest that FOLFIRI, a common regimen combining irinotecan and 5-FU, should switch the dosing sequence, namely from 5-FU to irinotecan, to enhance hydrolytic activation of irinotecan. This modified order likely reduces the dose of anti-cancer agents, thus minimizing overall toxicity. The results also conclude that p53 family members act differently in regulating gene expression.
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Affiliation(s)
- Da Xiao
- Department of Biomedical and Pharmaceutical Sciences, Center for Pharmacogenomics and Molecular Therapy, University of Rhode Island, Kingston, RI 02881, USA
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Di Paolo A, Polillo M, Lastella M, Bocci G, Del Re M, Danesi R. Methods: for studying pharmacogenetic profiles of combination chemotherapeutic drugs. Expert Opin Drug Metab Toxicol 2015; 11:1253-67. [PMID: 26037261 DOI: 10.1517/17425255.2015.1053460] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
INTRODUCTION Molecular and genetic analysis of tumors and individuals has led to patient-centered therapies, through the discovery and identification of genetic markers predictive of drug efficacy and tolerability. Present therapies often include a combination of synergic drugs, each of them directed against different targets. Therefore, the pharmacogenetic profiling of tumor masses and patients is becoming a challenge, and several questions may arise when planning a translational study. AREAS COVERED The review presents the different techniques used to stratify oncology patients and to tailor antineoplastic treatments according to individual pharmacogenetic profiling. The advantages of these methodologies are discussed as well as current limits. EXPERT OPINION Facing the rapid technological evolution for genetic analyses, the most pressing issues are the choice of appropriate strategies (i.e., from gene candidate up to next-generation sequencing) and the possibility to replicate study results for their final validation. It is likely that the latter will be the major obstacle in the future. However, the present landscape is opening up new possibilities, overcoming those hurdles that have limited result translation into clinical settings for years.
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Affiliation(s)
- Antonello Di Paolo
- University of Pisa, Department of Clinical and Experimental Medicine, Via Roma 55, 56126 Pisa , Italy +39 050 2218755 ; +39 050 2218758 ;
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Abstract
Diarrhoea induced by chemotherapy in cancer patients is common, causes notable morbidity and mortality, and is managed inconsistently. Previous management guidelines were based on poor evidence and neglect physiological causes of chemotherapy-induced diarrhoea. In the absence of level 1 evidence from randomised controlled trials, we developed practical guidance for clinicians based on a literature review by a multidisciplinary team of clinical oncologists, dietitians, gastroenterologists, medical oncologists, nurses, pharmacist, and a surgeon. Education of patients and their carers about the risks associated with, and management of, chemotherapy-induced diarrhoea is the foundation for optimum treatment of toxic effects. Adequate--and, if necessary, repeated--assessment, appropriate use of loperamide, and knowledge of fluid resuscitation requirements of affected patients is the second crucial step. Use of octreotide and seeking specialist advice early for patients who do not respond to treatment will reduce morbidity and mortality. In view of the burden of chemotherapy-induced diarrhoea, appropriate multidisciplinary research to assess meaningful endpoints is urgently required.
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Evaluation of the in vitro/in vivo potential of five berries (bilberry, blueberry, cranberry, elderberry, and raspberry ketones) commonly used as herbal supplements to inhibit uridine diphospho-glucuronosyltransferase. Food Chem Toxicol 2014; 72:13-9. [DOI: 10.1016/j.fct.2014.06.020] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Revised: 05/05/2014] [Accepted: 06/23/2014] [Indexed: 12/15/2022]
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Li M, Wang Z, Guo J, Liu J, Li C, Liu L, Shi H, Liu L, Li H, Xie C, Zhang X, Sun W, Fang S, Bi X. Clinical significance of UGT1A1 gene polymorphisms on irinotecan-based regimens as the treatment in metastatic colorectal cancer. Onco Targets Ther 2014; 7:1653-61. [PMID: 25285015 PMCID: PMC4181635 DOI: 10.2147/ott.s67867] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Purpose The primary aim of this research was to investigate the association between uridine diphosphate glucuronosyltransferase (UGT)1A1 gene polymorphisms and the toxicities of irinotecan-based regimens in Chinese patients with metastatic colorectal cancer. Methods The study analyzed the distribution of UGT1A1*28/*6 gene polymorphisms by polymerase chain reaction amplification and pyrosequencing. The adverse reactions and tumor response were evaluated according to National Cancer Institute Common Toxicity Criteria for Adverse Events, Version 3.0, and Response Evaluation Criteria In Solid Tumors, Version 1.0, criteria, respectively. The correlation between UGT1A1 gene polymorphisms and severe delayed diarrhea or neutropenia was analyzed. The influences of UGT1A1*6/*28 polymorphisms on response rate and progression-free survival were also analyzed. Survival analysis was performed by the Kaplan–Meier method, and we used the log-rank test to analyze the effect of genotypes on progression-free survival, the logistic regression model for multivariate analysis, and the Cox regression model for multivariate survival analysis. Results A total of 167 patients with metastatic colorectal cancer who were treated with irinotecan-based regimens and with detected UGT1A1 gene polymorphisms were enrolled in this research. The rate of UGT1A1*28 homozygous wild-type TA6/6, heterozygous mutant-type TA6/7, and homozygous mutant-type TA7/7 was 65.3% (109/167), 32.3% (54/167), and 2.4% (4/167), respectively; the incidence of UGT1A1*6 wild-type G/G was 67.1% (112/167), heterozygous mutant-type G/A accounted for 28.7% (48/167), and seven cases were homozygous mutant-type A/A (4.2%; 7/167). The incidence of grade 3 or 4 delayed diarrhea in patients carrying UGT1A1*6 (G/A and A/A) was higher than that in the wild-type (G/G) (P=0.021). The rate was significantly lower in patients with the UGT1A1*28 TA6/6 wide-type genotype than those with TA6/7 and TA7/7 mutant-type genotypes (P=0.027). However, neither UGT1A1*6 (P=0.34) nor UGT1A1*28 (P=0.232) variants were significantly associated with severe neutropenia. Our study found no significant differences of severe neutropenia in patients with different numbers of mutational alleles (P=0.354), but patients with two alleles or single allele variants had more chances to develop severe diarrhea than patients with wild-type (P=0.027). No significant differences of either response rate or progression-free survival were found among different genotypes (P>0.05). Conclusion For irinotecan-based regimens in metastatic colorectal cancer, the UGT1A1*28 and UGT1A1*6 locus mutations can be regarded as predictors for irinotecan-associated severe delayed diarrhea, whereas no association between UGT1A1 gene polymorphisms and severe neutropenia was observed. We also found that neither clinical response nor prognosis were significantly associated with UGT1A1 gene polymorphisms.
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Affiliation(s)
- Minmin Li
- School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Shandong, People's Republic of China
| | - Zhehai Wang
- Department of Oncology, Shandong Cancer Hospital, Shandong, People's Republic of China
| | - Jun Guo
- Department of Oncology, Shandong Cancer Hospital, Shandong, People's Republic of China
| | - Jie Liu
- Department of Oncology, Shandong Cancer Hospital, Shandong, People's Republic of China
| | - Changzheng Li
- Department of Oncology, Shandong Cancer Hospital, Shandong, People's Republic of China
| | - Lin Liu
- Department of Oncology, Shandong Cancer Hospital, Shandong, People's Republic of China
| | - Huan Shi
- Department of Oncology, Shandong Cancer Hospital, Shandong, People's Republic of China
| | - Liyan Liu
- Department of Oncology, Shandong Cancer Hospital, Shandong, People's Republic of China
| | - Huihui Li
- Department of Oncology, Shandong Cancer Hospital, Shandong, People's Republic of China
| | - Chao Xie
- Department of Oncology, Shandong Cancer Hospital, Shandong, People's Republic of China
| | - Xia Zhang
- Department of Oncology, Shandong Cancer Hospital, Shandong, People's Republic of China
| | - Wenwen Sun
- School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Shandong, People's Republic of China
| | - Shu Fang
- School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Shandong, People's Republic of China
| | - Xiang Bi
- School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Shandong, People's Republic of China
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Affiliation(s)
- Mitch A Phelps
- College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH
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Evaluation of the in vitro/in vivo drug interaction potential of BST204, a purified dry extract of ginseng, and its four bioactive ginsenosides through cytochrome P450 inhibition/induction and UDP-glucuronosyltransferase inhibition. Food Chem Toxicol 2014; 68:117-27. [DOI: 10.1016/j.fct.2014.03.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Revised: 02/27/2014] [Accepted: 03/01/2014] [Indexed: 11/24/2022]
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Ebrahimkhani MR, Neiman JAS, Raredon MSB, Hughes DJ, Griffith LG. Bioreactor technologies to support liver function in vitro. Adv Drug Deliv Rev 2014; 69-70:132-57. [PMID: 24607703 PMCID: PMC4144187 DOI: 10.1016/j.addr.2014.02.011] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Revised: 02/18/2014] [Accepted: 02/24/2014] [Indexed: 02/08/2023]
Abstract
Liver is a central nexus integrating metabolic and immunologic homeostasis in the human body, and the direct or indirect target of most molecular therapeutics. A wide spectrum of therapeutic and technological needs drives efforts to capture liver physiology and pathophysiology in vitro, ranging from prediction of metabolism and toxicity of small molecule drugs, to understanding off-target effects of proteins, nucleic acid therapies, and targeted therapeutics, to serving as disease models for drug development. Here we provide perspective on the evolving landscape of bioreactor-based models to meet old and new challenges in drug discovery and development, emphasizing design challenges in maintaining long-term liver-specific function and how emerging technologies in biomaterials and microdevices are providing new experimental models.
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Affiliation(s)
- Mohammad R Ebrahimkhani
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Jaclyn A Shepard Neiman
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Micha Sam B Raredon
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | | | - Linda G Griffith
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Center for Gynepathology Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
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Pharmacogenetics of ABC and SLC transporters in metastatic colorectal cancer patients receiving first-line FOLFIRI treatment. Pharmacogenet Genomics 2014; 23:549-57. [PMID: 24018773 DOI: 10.1097/fpc.0b013e328364b6cf] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Membrane transporters are widely recognized as important determinants of drug disposition and response, generating increasing interest on the pharmacological implications of their genetic variations. The aim of this study was to elucidate the predictive/prognostic role of ATP-binding cassette (ABC) and solute carrier (SLC) protein polymorphisms on irinotecan (FOLFIRI regimen) outcome. PATIENTS AND METHODS A total of 250 White metastatic colorectal cancer patients homogenously treated with a first-line FOLFIRI regimen were genotyped for a panel of variants in five transporter genes. The primary study endpoints were the response rate (partial or complete response), overall survival, and time to progression. Toxicity was considered a secondary endpoint. Irinotecan pharmacokinetic data of 71 patients were used for polymorphism functional analysis. RESULTS Two variants of the ABCG2 (-15622C>T, rs7699188) gene were found to be predictive (P < 0.01) of the response rate. High-order relationships of ABC/SLC markers with previously investigated genetic (UGT1A1 polymorphisms) and nongenetic (primary tumor site) factors that helped determine the response rate were highlighted. A prognostic effect of the ABCB1 rs2032582 variant on patient overall survival emerged (P = 0.0074). The ABCG2 rs7699788 variant was also seen to be associated with grade 3-4 nonhematological toxicity (P = 0.0012). The ABCG2 (-15622C>T, rs7699188) and ABCB1 (rs2032582) polymorphisms were not found to be associated with pharmacokinetic parameters. CONCLUSION This study showed that ABC/SLC polymorphisms have a crucial contribution toward the FOLFIRI outcome. This could represent a further step toward personalized therapy.
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Grassi L, Caruso R, Hammelef K, Nanni MG, Riba M. Efficacy and safety of pharmacotherapy in cancer-related psychiatric disorders across the trajectory of cancer care: a review. Int Rev Psychiatry 2014; 26:44-62. [PMID: 24716500 DOI: 10.3109/09540261.2013.842542] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
At least 25-30% of patients with cancer and an even higher percentage of patients in an advanced phase of illness meet the criteria for a psychiatric diagnosis, including depression, anxiety, stress-related syndromes, adjustment disorders, sleep disorders and delirium. A number of studies have accumulated over the last 35 years on the use of psychotropic drugs as a pillar in the treatment of psychiatric disorders. Major advances in psycho-oncology research have also shown the efficacy of psychotropic drugs as adjuvant treatment of cancer-related symptoms, such as pain, hot flushes, pruritus, nausea and vomiting, fatigue, and cognitive impairment. The knowledge about pharmacokinetics and pharmacodynamics, clinical use, safety, side effects and efficacy of psychotropic drugs in cancer care is essential for an integrated and multidimensional approach to patients treated in different settings, including community-based centres, oncology, and palliative care. A search of the major databases (MEDLINE, Embase, PsycLIT, PsycINFO, the Cochrane Library) was conducted in order to summarize relevant data concerning the efficacy and safety of pharmacotherapy for cancer-related psychiatric disorders in cancer patients across the trajectory of the disease.
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Affiliation(s)
- Luigi Grassi
- Institute of Psychiatry, Department of Biomedical and Specialty Surgical Sciences, University of Ferrara , Ferrara , Italy
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Xu JM, Wang Y, Ge FJ, Lin L, Liu ZY, Sharma MR. Severe irinotecan-induced toxicity in a patient with UGT1A1*28 and UGT1A1*6 polymorphisms. World J Gastroenterol 2013; 19:3899-3903. [PMID: 23840132 PMCID: PMC3699040 DOI: 10.3748/wjg.v19.i24.3899] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Revised: 04/24/2013] [Accepted: 05/10/2013] [Indexed: 02/06/2023] Open
Abstract
Many studies have demonstrated the impact of UGT1A1 on toxicity of irinotecan. In particular, patients bearing UGT1A1*28 (TA 7/7) have a higher risk of severe neutropenia and diarrhea. Based on this, prescribers of irinotecan are advised that patients with UGT1A1*28 (TA 7/7) should start with a reduced dose of irinotecan, although a particular dose is not specified. Research in Asian countries has shown a lower incidence of UGT1A1*28 (TA 7/7), while UGT1A1*6 (A/A) is more often found and is associated with severe irinotecan-related neutropenia. We report here a case of a metastatic colorectal cancer patient who is heterozygous for the UGT1A1*28 polymorphism (TA 6/7) as well as the UGT1A1*6 polymorphism (G/A). The patient was treated with FOLFIRI for 9 cycles and underwent two irinotecan dose reductions according to pharmacokinetic data regarding exposure to the active metabolite, SN-38. Simultaneous heterozygous UGT1A1*28 and UGT1A1*6 polymorphisms may produce higher exposure to SN-38 and a higher risk of adverse effects related to irinotecan. Additional studies will be necessary to determine the optimal starting dose of irinotecan for patients with both UGT1A1*28 and UGT1A1*6 polymorphisms.
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Use of pharmacogenetics for predicting cancer prognosis and treatment exposure, response and toxicity. J Hum Genet 2013; 58:346-52. [PMID: 23677053 DOI: 10.1038/jhg.2013.42] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Cancer treatment is complicated because of a multitude of treatment options and little patient-specific information to help clinicians choose appropriate therapy. There are two genomes relevant in cancer treatment: the tumor (somatic) and the patient (germline). Together, these two genomes dictate treatment outcome through four processes: the somatic genome primarily determines tumor prognosis and response while the germline genome modulates treatment exposure and toxicity. In this review, we describe the influence of these genomes on treatment outcomes by highlighting examples of genetic variation that are predictors of each of these four factors, prognosis, response, toxicity and exposure, and discuss the translation and clinical implementation of each. Use of pre-treatment pharmacogenetic testing will someday enable clinicians to make individualized therapy decisions about aggressiveness, drug selection and dose, improving treatment outcomes for cancer patients.
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Ma GY, Cao YF, Hu CM, Fang ZZ, Sun XY, Hong M, Zhu ZT. Comparison of Inhibition Capability of Scutellarein and Scutellarin Towards Important Liver UDP-Glucuronosyltransferase (UGT) Isoforms. Phytother Res 2013; 28:382-6. [PMID: 23620377 DOI: 10.1002/ptr.4990] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2013] [Revised: 03/07/2013] [Accepted: 03/08/2013] [Indexed: 12/13/2022]
Affiliation(s)
- Guang-You Ma
- The First Affiliated Hospital of Liaoning Medical University; Jinzhou 121001 China
| | - Yun-Feng Cao
- Joint Center for Translational Medicine, Dalian Institute of Chemical Physics Chinese Academy of sciences and The first Affiliated Hospital of Liaoning Medical University; No.457, Zhongshan Road Dalian 116023 China
| | - Cui-Min Hu
- The First Affiliated Hospital of Liaoning Medical University; Jinzhou 121001 China
- Joint Center for Translational Medicine, Dalian Institute of Chemical Physics Chinese Academy of sciences and The first Affiliated Hospital of Liaoning Medical University; No.457, Zhongshan Road Dalian 116023 China
| | - Zhong-Ze Fang
- The First Affiliated Hospital of Liaoning Medical University; Jinzhou 121001 China
- Joint Center for Translational Medicine, Dalian Institute of Chemical Physics Chinese Academy of sciences and The first Affiliated Hospital of Liaoning Medical University; No.457, Zhongshan Road Dalian 116023 China
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute; Bethesda Maryland 20892 USA
| | - Xiao-Yu Sun
- Joint Center for Translational Medicine, Dalian Institute of Chemical Physics Chinese Academy of sciences and The first Affiliated Hospital of Liaoning Medical University; No.457, Zhongshan Road Dalian 116023 China
| | - Mo Hong
- Joint Center for Translational Medicine, Dalian Institute of Chemical Physics Chinese Academy of sciences and The first Affiliated Hospital of Liaoning Medical University; No.457, Zhongshan Road Dalian 116023 China
| | - Zhi-Tu Zhu
- The First Affiliated Hospital of Liaoning Medical University; Jinzhou 121001 China
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A UGT1A1*28 and *6 genotype-directed phase I dose-escalation trial of irinotecan with fixed-dose capecitabine in Korean patients with metastatic colorectal cancer. Cancer Chemother Pharmacol 2013; 71:1609-17. [DOI: 10.1007/s00280-013-2161-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2012] [Accepted: 04/04/2013] [Indexed: 01/02/2023]
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Wang Y, Shen L, Xu N, Wang JW, Jiao SC, Liu ZY, Xu JM. UGT1A1 predicts outcome in colorectal cancer treated with irinotecan and fluorouracil. World J Gastroenterol 2012; 18:6635-44. [PMID: 23236239 PMCID: PMC3516223 DOI: 10.3748/wjg.v18.i45.6635] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2012] [Revised: 09/13/2012] [Accepted: 10/22/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate effects of UDP-glucuronosyltransferase1A1 (UGT1A1) and thymidylate synthetase (TS) gene polymorphisms on irinotecan in metastatic colorectal cancer (mCRC).
METHODS: Two irinotecan- and fluorouracil-based regimens, FOLFIRI and IFL, were selected as second-line therapy for 138 Chinese mCRC patients. Genomic DNA was extracted from peripheral blood samples before treatment. UGT1A1 and TS gene polymorphisms were determined by direct sequencing and restriction fragment length polymorphism, respectively. Gene polymorphisms of UGT1A1*28, UGT1A1*6 and promoter enhancer region of TS were analyzed. The relationship between genetic polymorphisms and clinical outcome, that is, response, toxicity and survival were assessed. Pharmacokinetic analyses were performed in a subgroup patients based on different UGT1A1 genotypes. Plasma concentration of irinotecan and its active metabolite SN-38 and inactive metabolite SN-38G were determined by high performance liquid chromatography. Differences in irinotecan and its metabolites between UGT1A1 gene variants were compared.
RESULTS: One hundred and eight patients received the FOLFIRI regimen, 29 the IFL regimen, and one irinotecan monotherapy. One hundred and thirty patients were eligible for toxicity and 111 for efficacy evaluation. One hundred and thirty-six patients were tested for UGT1A1*28 and *6 genotypes and 125 for promoter enhancer region of TS. Patients showed a higher frequency of wild-type UGT1A1*28 (TA6/6) compared with a Caucasian population (69.9% vs 45.2%). No significant difference was found between response rates and UGT1A1 genotype, although wild-type showed lower response rates compared with other variants (17.9% vs 24.2% for UGT1A1*28, 15.7% vs 26.8% for UGT1A1*6). When TS was considered, the subgroup with homozygous UGT1A1*28 (TA7/7) and non-3RG genotypes showed the highest response rate (33.3%), while wild-type UGT1A1*28 (TA6/6) with non-3RG only had a 13.6% response rate, but no significant difference was found. Logistic regression showed treatment duration was closely linked to clinical response. In toxicity comparison, UGT1A1*28 TA6/6 was associated with lower incidence of grade 2-4 diarrhea (27.8% vs 100%), and significantly reduced the risk of grade 4 neutropenia compared with TA7/7 (7.8% vs 37.5%). Wild-type UGT1A1*6 (G/G) tended to have a lower incidence of grade 3/4 diarrhea vs homozygous mutant (A/A) genotype (13.0% vs 40.0%). Taking UGT1A1 and TS genotypes together, lower incidence of grade 2-4 diarrhea was found in patients with non-3RG TS genotypes, when TA6/6 was compared with TA7/7 (35.3% vs 100.0%). No significant association with time to progression (TTP) and overall survival (OS) was observed with either UGT1A1 or TS gene polymorphisms, although slightly longer TTP and OS were found with UGT1A1*28 (TA6/6). Irinotecan PK was investigated in 34 patients, which showed high area under concentration curve (AUC) of irinotecan and SN-38, but low AUC ratio (SN-38G / SN-38) in those patients with UGT1A1*28 TA7/7.
CONCLUSION: A distinct distribution pattern of UGT1A1 genotypes in Chinese patients might contribute to relatively low toxicity associated with irinotecan and 5-fluorouracil in mCRC patients.
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Abstract
Detailed knowledge regarding the influence of hepatic transport proteins on drug disposition has advanced at a rapid pace over the past decade. Efflux transport proteins located in the basolateral and apical (canalicular) membranes of hepatocytes play an important role in the hepatic elimination of many endogenous and exogenous compounds, including drugs and metabolites. This review focuses on the role of these efflux transporters in hepatic drug excretion. The impact of these proteins as underlying factors for disease is highlighted, and the importance of hepatic efflux proteins in the efficacy and toxicity of drugs is discussed. In addition, a brief overview of methodology to evaluate the function of hepatic efflux transport proteins is provided. Current challenges in predicting the impact of altered efflux protein function on systemic, intestinal, and hepatocyte exposure to drugs and metabolites are highlighted.
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Liu HL, Li ZY, Liu YF, Li HY, Yu ZH. Irinotecan-related cholinergic symptoms in patients with colorectal cancer patients: an analysis of 89 cases. Shijie Huaren Xiaohua Zazhi 2012; 20:975-979. [DOI: 10.11569/wcjd.v20.i11.975] [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] [Indexed: 02/06/2023] Open
Abstract
AIM: To observe and analyze irinotecan-related cholinergic symptoms in patients with advanced colorectal cancer.
METHODS: A total of 89 patients with advanced colorectal cancer were assigned to receive two different FOLFIRI regimens. The incidence of cholinergic symptoms was recorded, and the correlation of the development of cholinergic symptoms with clinical characteristics, other adverse effects and chemotherapy regimens was analyzed.
RESULTS: Fifty-three patients developed cholinergic symptoms. From the start of infusion, cholinergic symptoms occurred at a median of 150 min (range: 30 min-25 h) and most of them regressed in 24 h. Prophylactic use of atropine could effectively prevent the development of cholinergic symptoms. Cholinergic symptoms were more common in senile patients (75.9% vs 51.7%, P = 0.029), but were not related with other clinical characteristics such as sex and ECOG score. Patients who developed cholinergic symptoms had a decreasing tendency to develop delayed-onset diarrhea. The regimen containing higher dose of fluorouracil was associated with a higher risk of developing mucocitis (50.0% vs 27.5%, P = 0.029).
CONCLUSION: The incidence rate of irinotecan-related cholinergic symptoms is unexpectedly high. The development of irinotecan-related cholinergic symptoms is not related with other adverse effects such as diarrhea and/or bone marrow depression.
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Chen X, Peer CJ, Alfaro R, Tian T, Spencer SD, Figg WD. Quantification of irinotecan, SN38, and SN38G in human and porcine plasma by ultra high-performance liquid chromatography-tandem mass spectrometry and its application to hepatic chemoembolization. J Pharm Biomed Anal 2012; 62:140-8. [PMID: 22305081 PMCID: PMC3288457 DOI: 10.1016/j.jpba.2012.01.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2011] [Revised: 01/05/2012] [Accepted: 01/08/2012] [Indexed: 12/30/2022]
Abstract
An analytical method was developed and validated for the quantitative determination of irinotecan, its active metabolite SN38, and glucuronidated SN38 (SN38-G) in both porcine and human plasma. Calibration curves were linear within the concentration range of 0.5-100 ng/mL for SN38 and SN38-G, and 5-1000 ng/mL for irinotecan. Sample pretreatment involved solid-phase extraction of 0.1 mL aliquots of plasma. Irinotecan, SN38, SN38-G, and the internal standards, irinotecan-d10, tolbutamide, and camptothecin, respectively, were separated on a Waters ACQUITY UPLC BEH RP18 column (2. 1mm × 50 mm, 1.7 μm), using a mobile phase composed of methanol and 0.1% formic acid. Accuracy of quality control samples in human plasma ranged from 98.5 to 110.3%, 99.5 to 101.7% and 96.2 to 98.9% for irinotecan, SN38, and SN38-G, respectively. Precision of the three analytes in the same order ranged from 0.8 to 2.8%, 2.4 to 5.7%, and 2.4 to 2.8%. All three analytes proved stable in plasma through four freeze/thaw cycles, as well as through 6h in whole blood at room temperature. The method was likewise validated in porcine plasma with comparable accuracies and precisions also within the generally acceptable range. The validated method was applied to both preclinical and clinical trials involving hepatic chemoembolization of irinotecan drug-eluting beads to study the pharmacokinetics of the three analytes.
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Affiliation(s)
- Xiaohong Chen
- Clinical Pharmacology Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD 21702, USA
| | - Cody J. Peer
- Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Raul Alfaro
- Pharmacy Section, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
| | - Tian Tian
- Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Shawn D. Spencer
- Clinical Pharmacology Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD 21702, USA
| | - William D. Figg
- Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
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