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Akyel YK, Seyhan NO, Gül Ş, Çelik M, Taşkın AC, Selby CP, Sancar A, Kavakli IH, Okyar A. The impact of circadian rhythm disruption on oxaliplatin tolerability and pharmacokinetics in Cry1 -/-Cry2 -/- mice under constant darkness. Arch Toxicol 2025; 99:1417-1429. [PMID: 39903276 PMCID: PMC11968489 DOI: 10.1007/s00204-025-03968-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 01/15/2025] [Indexed: 02/06/2025]
Abstract
Circadian rhythms, the 24-h oscillations of biological activities guided by the molecular clock, play a pivotal role in regulating various physiological processes in organisms. The intricate relationship between the loss of circadian rhythm and its influence on the tolerability and pharmacokinetic properties of anticancer drugs is poorly understood. In our study, we investigated the effects of oxaliplatin, a commonly used anticancer drug, on Cry1-/- and Cry2-/- mice (Cry DKO mice) under darkness conditions, where they exhibit free-running phenotype. We administered oxaliplatin at a dosage of 12 mg/kg/day at two distinct circadian times, CT8 and CT16, under constant darkness conditions to Cry DKO mice and their wild type littermates. Our results revealed a striking disparity in oxaliplatin tolerance between Cry DKO mice and their wild-type counterparts. Oxaliplatin exhibited severe toxicity in Cry DKO mice at both CT8 and CT16, in contrast to the wild type mice. Pharmacokinetic analyses suggested that such toxicity was a result of high concentrations of oxaliplatin in the serum and liver of Cry DKO mice after repeated dose injections. To understand the molecular basis of such intolerance, we performed RNA-seq studies using mouse livers. Our findings from the RNA-seq analysis highlighted the substantial impact of circadian rhythm disruption on gene expression, particularly affecting genes involved in detoxification and xenobiotic metabolism, such as the Gstm gene family. This dysregulation in detoxification pathways in Cry DKO mice likely contributes to the increased toxicity of oxaliplatin. In conclusion, our study highlights the crucial role of an intact molecular clock in dictating the tolerability of oxaliplatin. These findings emphasize the necessity of considering circadian rhythms in the administration of anticancer drugs, providing valuable insights into optimizing treatment strategies for cancer patients.
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Affiliation(s)
- Yasemin Kubra Akyel
- Department of Medical Pharmacology, School of Medicine, Istanbul Medipol University, Istanbul, Türkiye
- Department of Pharmacology, Faculty of Pharmacy, Istanbul University, TR-34116, Beyazit-Istanbul, Türkiye
| | - Narin Ozturk Seyhan
- Department of Pharmacology, Faculty of Pharmacy, Istanbul University, TR-34116, Beyazit-Istanbul, Türkiye
| | - Şeref Gül
- Biotechnology Division, Department of Biology, Faculty of Science, Istanbul University, Istanbul, Türkiye
- Institute of Life Sciences and Biotechnology, Bezmialem Vakif University, Istanbul, Türkiye
| | - Melis Çelik
- Department of Molecular Biology and Genetics, Koc University, Istanbul, Türkiye
| | - Ali Cihan Taşkın
- Department of Laboratory Animal Science, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Türkiye
- Translational Medicine Research Center, Experimental Animals Laboratory, Koc University, Istanbul, Türkiye
| | - Christopher P Selby
- Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Aziz Sancar
- Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Ibrahim Halil Kavakli
- Department of Molecular Biology and Genetics, Koc University, Istanbul, Türkiye.
- Department of Chemical and Biological Engineering, Koc University, Istanbul, Türkiye.
| | - Alper Okyar
- Department of Pharmacology, Faculty of Pharmacy, Istanbul University, TR-34116, Beyazit-Istanbul, Türkiye.
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Johnson AC, Tsitsikov EN, Phan KP, Zuccato JA, Bauer AM, Graffeo CS, Hameed S, Stephens TM, Liu Y, Dunn GP, Tsytsykova AV, Jones PS, Dunn IF. GSTM1 null genotype underpins recurrence of NF2 meningiomas. Front Oncol 2024; 14:1506708. [PMID: 39726707 PMCID: PMC11669715 DOI: 10.3389/fonc.2024.1506708] [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: 10/06/2024] [Accepted: 11/25/2024] [Indexed: 12/28/2024] Open
Abstract
Introduction Meningiomas are the most common primary central nervous system (CNS) tumor in adults, comprising one-third of all primary adult CNS tumors. Although several recent publications have identified molecular alterations in meningioma including characteristic mutations, copy number alterations, and gene expression signatures, our understanding of the drivers of meningioma recurrence is limited. Objective To identify gene expression signatures of 1p-22q-NF2- meningioma recurrence, with concurrent biallelic inactivation of NF2 and loss of chr1p that are heterogenous but enriched for recurrent meningiomas. Methods Transcriptomic alterations present in recurrent versus primary 1p-22q-NF2- meningiomas were identified using RNA sequencing (RNA-seq) data in a clinically annotated cohort. Results Recurrent 1p-22q-NF2- meningiomas were enriched for a newly identified GSTM1 null genotype compared to primary meningiomas that showed variable GSTM1 expression and independent external validation was performed. Conclusions The GSTM1 null genotype is a novel biomarker of 1p-22q-NF2- meningioma recurrence that resolves heterogeneity in existing meningioma subtypes and may be used to guide future clinical management decisions on extent of treatment to improve patient outcomes.
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Affiliation(s)
- Anthony C. Johnson
- Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Erdyni N. Tsitsikov
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Khanh P. Phan
- Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Jeffrey A. Zuccato
- Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Andrew M. Bauer
- Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Christopher S. Graffeo
- Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Sanaa Hameed
- Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Tressie M. Stephens
- Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Yufeng Liu
- Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
| | - Gavin P. Dunn
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Alla V. Tsytsykova
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Pamela S. Jones
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Ian F. Dunn
- Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
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Stojkovic Lalosevic M, Coric V, Pekmezovic T, Simic T, Pavlovic Markovic A, Pljesa Ercegovac M. GSTM1 and GSTP1 Polymorphisms Affect Outcome in Colorectal Adenocarcinoma. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:553. [PMID: 38674199 PMCID: PMC11052438 DOI: 10.3390/medicina60040553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 03/20/2024] [Accepted: 03/24/2024] [Indexed: 04/28/2024]
Abstract
Background and Objectives: Despite improvements in screening programs, a large number of patients with colorectal cancer (CRC) are diagnosed in an advanced disease stage. Previous investigations imply that glutathione transferases (GSTs) might be associated with the development and progression of CRC. Moreover, the detoxification mechanism of oxaliplatin, which represents the first line of treatment for advanced CRC, is mediated via certain GSTs. The aim of this study was to evaluate the significance of certain GST genetic variants on CRC prognosis and the efficacy of oxaliplatin-based treatment. Materials and Methods: This prospective study included 523 patients diagnosed with CRC in the period between 2014 and 2016, at the Digestive Surgery Clinic, University Clinical Center of Serbia, Belgrade. Patients were followed for a median of 43.47 ± 17.01 months (minimum 1-63 months). Additionally, 109 patients with advanced disease, after surgical treatment, received FOLFOX6 treatment as a first-line therapy between 2014 and 2020. The Kaplan-Meier method was used to analyze cumulative survival, and the Cox proportional hazard regression model was used to study the effects of different GST genotypes on overall survival. Results: Individuals with the GSTM1-null genotype and the GSTP1 IleVal+ValVal (variant) genotype had significantly shorter survival when compared to referent genotypes (GSTM1-active and GSTP1 IleIle) (log-rank: p = 0.001). Moreover, individuals with the GSTM1-null genotype who received 5-FU-based treatment had statistically significantly shorter survival when compared to individuals with the GSTM1-active genotype (log-rank: p = 0.05). Conclusions: Both GSTM1-null and GSTP1 IleVal+ValVal (variant) genotypes are associated with significantly shorter survival in CRC patients. What is more, the GSTM1-null genotype is associated with shorter survival in patients receiving FOLOFOX6 treatment.
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Affiliation(s)
- Milica Stojkovic Lalosevic
- Clinic of Gastroenterology and Hepatology, University Clinical Center of Serbia, 11000 Belgrade, Serbia;
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (V.C.); (T.P.); (T.S.)
| | - Vesna Coric
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (V.C.); (T.P.); (T.S.)
- Institute of Medical and Clinical Biochemistry, 11000 Belgrade, Serbia
| | - Tatjana Pekmezovic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (V.C.); (T.P.); (T.S.)
- Institute of Epidemiology, 11000 Belgrade, Serbia
| | - Tatjana Simic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (V.C.); (T.P.); (T.S.)
- Institute of Medical and Clinical Biochemistry, 11000 Belgrade, Serbia
| | - Aleksandra Pavlovic Markovic
- Clinic of Gastroenterology and Hepatology, University Clinical Center of Serbia, 11000 Belgrade, Serbia;
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (V.C.); (T.P.); (T.S.)
| | - Marija Pljesa Ercegovac
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (V.C.); (T.P.); (T.S.)
- Institute of Medical and Clinical Biochemistry, 11000 Belgrade, Serbia
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Nakanishi G, Pita-Oliveira M, Bertagnolli LS, Torres-Loureiro S, Scudeler MM, Cirino HS, Chaves ML, Miwa B, Rodrigues-Soares F. Worldwide Systematic Review of GSTM1 and GSTT1 Null Genotypes by Continent, Ethnicity, and Therapeutic Area. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2022; 26:528-541. [PMID: 36112350 DOI: 10.1089/omi.2022.0090] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Glutathione S-transferase Mu 1 (GSTM1) and glutathione S-transferase theta 1 (GSTT1) enzymes are glutathione-S-transferases with broad significance for susceptibility or resistance to multifactorial human diseases, as well as detoxification of environmental chemicals and drugs. Moreover, some individuals may have a complete deletion of GSTM1 and GSTT1 genes, which can contribute to patient-to-patient variability in drug safety and efficacy. GSTM1 and GSTT1 gene deletion frequencies can vary according to ethnicity and continental origin of the studied population with implications for achieving the goal of precision/personalized medicine in clinical practice. We report here a worldwide systematic review of the null genotypes in these two clinically important genes by continents, ethnicities, and therapeutic areas (TAs). Searches were performed in the PubMed database covering the period from 1992 to 2020. Out of the 1925 articles included, most studies analyzed European individuals, corroborating the literature failure for not adequately considering the non-European ethnicities. The frequency of GSTM1 and GSTT1 null genotypes was higher in patients than in healthy volunteers. Conversely, in East Asians, higher frequencies of the null genotypes were observed in healthy volunteers than patients. Oncology was the most intensively studied TA (57% of the articles) in relation to GSTM1 and GSTT1. In all, these results demonstrate that there is an important gap in the literature in terms of failure to consider a broader range of populations, as well as diseases wherein GSTM1 and GSTT1 variations have clinical and biological implications. To achieve precision/personalized medicine on a global/worldwide scale, with equity and inclusiveness, this knowledge/research gap ought to be remedied in studies of GSTM1 and GSTT1 null genotypes. To the best of our knowledge, this is the largest systematic review conducted to date addressing the GSTM1 and GSTT1 null genotypes worldwide. The analyses from the 1925 articles highlighted the current knowledge gaps in different TAs, ethnicities, and populations. Filling these gaps is of importance, given the role these genes play in relation to the metabolism of substances to which we have frequent contact with, the associations observed between their deletion and diseases such as cancer, in addition to the interethnic differences observed for the deletion frequencies of these genes.
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Affiliation(s)
- Giovana Nakanishi
- Departamento de Patologia, Genética e Evolução, Instituto de Ciências Biológicas e Naturais, Universidade Federal do Triângulo Mineiro, Uberaba, Brazil
| | - Murilo Pita-Oliveira
- Departamento de Patologia, Genética e Evolução, Instituto de Ciências Biológicas e Naturais, Universidade Federal do Triângulo Mineiro, Uberaba, Brazil
| | - Laísa S Bertagnolli
- Departamento de Patologia, Genética e Evolução, Instituto de Ciências Biológicas e Naturais, Universidade Federal do Triângulo Mineiro, Uberaba, Brazil
| | - Sabrina Torres-Loureiro
- Departamento de Patologia, Genética e Evolução, Instituto de Ciências Biológicas e Naturais, Universidade Federal do Triângulo Mineiro, Uberaba, Brazil
| | - Mariana M Scudeler
- Departamento de Patologia, Genética e Evolução, Instituto de Ciências Biológicas e Naturais, Universidade Federal do Triângulo Mineiro, Uberaba, Brazil
| | - Heithor S Cirino
- Departamento de Patologia, Genética e Evolução, Instituto de Ciências Biológicas e Naturais, Universidade Federal do Triângulo Mineiro, Uberaba, Brazil
| | - Maria Laura Chaves
- Departamento de Patologia, Genética e Evolução, Instituto de Ciências Biológicas e Naturais, Universidade Federal do Triângulo Mineiro, Uberaba, Brazil
| | - Bruno Miwa
- Departamento de Patologia, Genética e Evolução, Instituto de Ciências Biológicas e Naturais, Universidade Federal do Triângulo Mineiro, Uberaba, Brazil
| | - Fernanda Rodrigues-Soares
- Departamento de Patologia, Genética e Evolução, Instituto de Ciências Biológicas e Naturais, Universidade Federal do Triângulo Mineiro, Uberaba, Brazil
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Pozzi E, Alberti P. Management of Side Effects in the Personalized Medicine Era: Chemotherapy-Induced Peripheral Neurotoxicity. Methods Mol Biol 2022; 2547:95-140. [PMID: 36068462 DOI: 10.1007/978-1-0716-2573-6_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Pharmacogenomics is a powerful tool to predict individual response to treatment, in order to personalize therapy, and it has been explored extensively in oncology practice. Not only efficacy on the malignant disease has been investigated but also the possibility to predict adverse effects due to drug administration. Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of those. This potentially severe and long-lasting/permanent side effect of commonly administered anticancer drugs can severely impair quality of life (QoL) in a large cohort of long survival patients. So far, a pharmacogenomics-based approach in CIPN regard has been quite delusive, making a methodological improvement warranted in this field of interest: even the most refined genetic analysis cannot be effective if not applied correctly. Here we try to devise why it is so, suggesting how THE "bench-side" (pharmacogenomics) might benefit from and should cooperate with THE "bed-side" (clinimetrics), in order to make genetic profiling effective if applied to CIPN.
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Affiliation(s)
- Eleonora Pozzi
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
- NeuroMI (Milan Center for Neuroscience), Milan, Italy
| | - Paola Alberti
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
- NeuroMI (Milan Center for Neuroscience), Milan, Italy.
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J VP, A P. Virtual screening of mutations in antioxidant genes and its putative association with HNSCC: An in silico approach. Mutat Res 2020; 821:111710. [PMID: 32593872 DOI: 10.1016/j.mrfmmm.2020.111710] [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] [Received: 07/12/2019] [Revised: 04/04/2020] [Accepted: 05/19/2020] [Indexed: 01/10/2023]
Abstract
Abnormalities in the antioxidant pathway are usually associated with inflammatory conditions, followed by tissue damage. Cancer is one such disease where there is a build-up of reactive oxygen species leading to pathological consequences. The present study aims to identify the alteration in genes and proteins associated with the common antioxidant pathways among patients with head and neck squamous cell carcinoma (HNSCC). The study design follows a retrospective approach and employs computational tools to analyse the possible role of genes involved in the anti-oxidation pathways in patients with HNSCC. The TCGA PanCancer Atlas dataset was used for the analysis. The Oncoprint data were analysed further to obtain information on the type of gene alterations encountered in the HNSCC cases. Gene amplification and deletions were commonly observed in genes of the thiol reductase pathway, whereas substitutions leading to missense, frameshifts were found in the other pathways assessed. Gene encoding ceruloplasmin was found to harbor nucleotide variations in about 10 % of the patients with OSCC. An exhaustive knowledge of the molecular genetic mechanisms underlying the pathways identified can open new avenues in selecting candidate genes which can be used as therapeutic targets against HNSCC. The present work identifies and nominates crucial genes from the antioxidant system for further in vitro experiments.
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Affiliation(s)
- Vijayashree Priyadharsini J
- Biomedical Research Unit and Laboratory Animal Centre (BRULAC) - Dental Research Cell (DRC), Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Poonamallee High Road, Chennai 600 077, Tamil Nadu, India.
| | - Paramasivam A
- Biomedical Research Unit and Laboratory Animal Centre (BRULAC) - Dental Research Cell (DRC), Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Poonamallee High Road, Chennai 600 077, Tamil Nadu, India
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Wang H, Jiang H, Corbet C, de Mey S, Law K, Gevaert T, Feron O, De Ridder M. Piperlongumine increases sensitivity of colorectal cancer cells to radiation: Involvement of ROS production via dual inhibition of glutathione and thioredoxin systems. Cancer Lett 2019; 450:42-52. [PMID: 30790679 DOI: 10.1016/j.canlet.2019.02.034] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 02/08/2019] [Accepted: 02/14/2019] [Indexed: 01/19/2023]
Abstract
Piperlongumine (PL), naturally synthesized in long pepper, is known to selectively kill tumor cells via perturbation of reactive oxygen species (ROS) homeostasis. ROS are the primary effector molecules of radiation, and increase of ROS production by pharmacological modulation is known to enhance radioresponse. We therefore investigated the radiosensitizing effect of PL in colorectal cancer cells (CT26 and DLD-1) and CT26 tumor-bearing mice. Firstly, we found that PL induced excessive production of ROS due to depletion of glutathione and inhibition of thioredoxin reductase. Secondly, PL enhanced both the intrinsic and hypoxic radiosensitivity of tumor cells, linked to ROS-mediated increase of DNA damage, G2/M cell cycle arrest, and inhibition of cellular respiration. Finally, the radiosensitizing effect of PL was verified in vivo. PL improved the tumor response to both single and fractionated radiation, resulting in a significant increase of survival rate of tumor-bearing mice, while it was ineffective on its own. In line with in vitro findings, enhanced radioresponse is associated with inhibition of antioxidant systems. In conclusion, our results suggest that PL could be a potential radiosensitizer in colorectal cancer.
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Affiliation(s)
- Hui Wang
- Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Heng Jiang
- Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Cyril Corbet
- Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium
| | - Sven de Mey
- Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Kalun Law
- Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Thierry Gevaert
- Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Olivier Feron
- Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium
| | - Mark De Ridder
- Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
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Liu H, Shi W, Zhao L, Dai D, Gao J, Kong X. Can GSTM1 and GSTT1 polymorphisms predict clinical outcomes of chemotherapy in gastric and colorectal cancers? A result based on the previous reports. Onco Targets Ther 2016; 9:3683-94. [PMID: 27382306 PMCID: PMC4922816 DOI: 10.2147/ott.s105158] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Background Gastric and colorectal cancers remain the major causes of cancer-related death. Although chemotherapy improves the prognosis of the patients with gastrointestinal cancers, some patients do not benefit from therapy and are exposed to the adverse effects. The polymorphisms in genes including GSTM1 and GSTT1 have been explored to predict therapeutic efficacy; however, the results were inconsistent and inconclusive. Materials and methods A systematic review and meta-analysis was performed by searching relevant studies about the association between the GSTM1 and GSTT1 polymorphisms and chemotherapy efficacy in gastrointestinal cancers in databases such as PubMed, EMBASE, Web of Science, Chinese National Knowledge Infrastructure, and Wanfang database up to January 10, 2016. Subgroup analyses were also performed according to ethnicity, cancer type, evaluation criteria, study type, chemotherapy type, and age. Results A total of 19 articles containing 3,217 cases were finally included. Overall analysis suggested that no significance was found between overall toxicity, neurotoxicity, neutropenia, gastrointestinal toxicity, tumor response, and progression-free survival, and the polymorphisms in GSTM1 and GSTT1, while GSTM1 polymorphism associated with overall survival (OS; hazard ratio =1.213, 95% confidence interval =1.060–1.388, P=0.005). Subgroup analyses suggested that neurotoxicity was associated with GSTM1 polymorphism in the Asian population, neutropenia was associated with GSTM1 polymorphism in palliative chemotherapy and older patients (mean age >60 years), and tumor response was associated with GSTT1 polymorphism in gastric cancer and responders defined by complete and partial responses. Meanwhile, GSTM1 was associated with OS in Caucasians, Asians, those with colorectal cancer, and patients with mean age <60 years. GSTT1 polymorphism was also associated with OS in Caucasians and patients with mean age >60 years. Conclusion The polymorphisms in GSTM1 and GSTT1 did not associate with the chemotherapy-related toxicity in gastrointestinal cancers, while GSTT1 polymorphism associated with OS, and further well-designed, larger-scale epidemiological studies are needed to validate our results.
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Affiliation(s)
| | - Wei Shi
- Office of Medical Statistics
| | | | | | | | - Xiangjun Kong
- Central Laboratory, Cangzhou Central Hospital, Yunhe District, Cangzhou, People's Republic of China
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Zhai XH, Huang J, Wu FX, Zhu DY, Wang AC. Impact of XRCC1, GSTP1, and GSTM1 Polymorphisms on the Survival of Ovarian Carcinoma Patients Treated with Chemotherapy. Oncol Res Treat 2016; 39:440-6. [DOI: 10.1159/000447337] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Accepted: 06/02/2016] [Indexed: 11/19/2022]
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Shen X, Wang J, Yan X, Ren X, Wang F, Chen X, Xu Y. Predictive value of GSTP1 Ile105Val polymorphism in clinical outcomes of chemotherapy in gastric and colorectal cancers: a systematic review and meta-analysis. Cancer Chemother Pharmacol 2016; 77:1285-302. [PMID: 27154175 DOI: 10.1007/s00280-016-3047-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2016] [Accepted: 04/25/2016] [Indexed: 12/16/2022]
Abstract
PURPOSE Gastric and colorectal cancers remain the major causes of cancer-related death with a bad prognosis. Up to now, platinum combined with fluoropyrimidines has been most commonly used in chemotherapy regimens of gastric and colorectal cancers. Recently, a series of studies have been conducted to investigate the associations of biomarkers, such as GSTP1 Ile105Val polymorphism, with the chemotherapy efficacy in gastric and colorectal cancers; however, the results were not consistent and inconclusive. Here, we performed a systematic review and meta-analysis to summarize the associations of GSTP1 Ile105Val polymorphism with the chemotherapy efficacy in gastric and colorectal cancers. METHODS A systematic review was conducted to search relevant studies in English databases (PubMed, ISI Web of Science, and EMBASE) up to November 30, 2015. The pooling ORs or HRs were used to assess the strength of the associations of GSTP1 Ile105Val polymorphism with clinical outcomes such as tumor response, toxicity, progression-free survival (PFS), and overall survival (OS). RESULTS Forty-one papers containing 8169 cases were finally included in the present meta-analysis study. Of which, 28 articles were performed in colorectal cancers, one in gastrointestinal carcinoma (gastric and colon cancer), 11 in gastric cancers, and one in colorectal and gastroesophageal cancers. After pooling all the eligible studies, we identified significant associations of GSTP1 Ile105Val polymorphism with chemotherapy-related tumor response (G vs. A: OR 1.697, 95 % CI 1.191-2.418; GG vs. AA: OR 2.804, 95 % CI 1.414-5.560; AG vs. AA: OR 1.540, 95 % CI 1.011-2.347; GG vs. AAAG: OR 2.139, 95 % CI 1.256-3.641), PFS (GG vs. AA, HR 0.640, 95 % CI 0.455-0.900; AGGG vs. AA: HR 0.718, 95 % CI 0.562-0.919), and OS (AG vs. AA: HR 0.857, 95 % CI 0.746-0.986; GG vs. AA: HR 0.679, 95 % CI 0.523-0.882; AGGG vs. AA: HR 0.663, 95 % CI 0.542-0.812) in gastric and colorectal cancers and no significant association was found between the polymorphism with toxicity. CONCLUSIONS GSTP1 Ile105Val polymorphism was associated with tumor response, PFS, and OS in gastric and colorectal cancers after chemotherapy.
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Affiliation(s)
- Xiaobing Shen
- School of Public Health, Southeast University, No. 87, Dingjiaqiao Road, Nanjing, 21000, China.
| | - Jia Wang
- School of Public Health, Southeast University, No. 87, Dingjiaqiao Road, Nanjing, 21000, China
| | - Xiaoluan Yan
- School of Public Health, Southeast University, No. 87, Dingjiaqiao Road, Nanjing, 21000, China
| | - Xiaofeng Ren
- School of Public Health, Southeast University, No. 87, Dingjiaqiao Road, Nanjing, 21000, China
| | - Fan Wang
- School of Public Health, Southeast University, No. 87, Dingjiaqiao Road, Nanjing, 21000, China
| | - Xiaowei Chen
- School of Public Health, Southeast University, No. 87, Dingjiaqiao Road, Nanjing, 21000, China
| | - Yuchao Xu
- School of Public Health, Southeast University, No. 87, Dingjiaqiao Road, Nanjing, 21000, China
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CONG LANXIANG, ZHAI XIANGHONG, WU FENGXIA, ZHU DONGYI, WANG ANCONG. Single nucleotide polymorphisms in glutathione S-transferase P1 and M1 genes and overall survival of patients with ovarian serous cystadenocarcinoma treated with chemotherapy. Oncol Lett 2016; 11:2525-2531. [DOI: 10.3892/ol.2016.4223] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 01/04/2016] [Indexed: 11/05/2022] Open
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12
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Glutathione S-transferase M1 null genotype related to poor prognosis of colorectal cancer. Tumour Biol 2016; 37:10229-34. [DOI: 10.1007/s13277-015-4676-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Accepted: 12/16/2015] [Indexed: 12/11/2022] Open
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13
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Liu P, Zhang M, Xie X, Jin J, Holman CDJ. Green tea consumption and glutathione S-transferases genetic polymorphisms on the risk of adult leukemia. Eur J Nutr 2015; 56:603-612. [PMID: 26578531 DOI: 10.1007/s00394-015-1104-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Accepted: 11/10/2015] [Indexed: 01/05/2023]
Abstract
PURPOSE Green tea may have a beneficial role of inhibiting leukemia. Glutathione S-transferases (GSTs) are known to detoxify certain carcinogens. We investigated the roles of green tea consumption and polymorphisms of GSTM1, GSTT1 and GSTP1 on the risk of adult leukemia, and to determine whether the associations varied within GSTs genotypes. METHODS A multicenter case-control study was conducted in China, 2008-2013. It comprised 442 incident, hematologically confirmed adult leukemia cases and 442 outpatient controls, individually matched to cases by gender, birth quinquennium and study site. Data were collected by face-to-face interview using a validated questionnaire. Genetic polymorphisms were assayed by PCR. RESULTS An inverse association between green tea consumption and adult leukemia risk was observed. Compared with non-tea drinkers, the adjusted odds ratios (95 % confidence intervals) were 0.50 (0.27-0.93), 0.31 (0.17-0.55) and 0.53 (0.29-0.99) for those who, respectively, consumed green tea >20 years, ≥2 cups daily and dried tea leaves >1000 g annually. In assessing the associations by GSTs genotypes, risk reduction associated with green tea consumption was stronger in individuals with the GSTT1-null genotype (OR 0.24; 95 % CI 0.11-0.53) than GSTT1-normal carriers (OR 0.67; 95 % CI 0.42-1.05; P interaction = 0.02). GSTM1 and GSTP1 did not significantly modify the inverse association of leukemia with green tea. CONCLUSIONS The results suggest that regular daily green tea consumption may reduce leukemia risk in Chinese adults regardless of GSTM1 and GSTP1 polymorphic status. The association between green tea and adult leukemia risk varied with GSTT1 genotype and highlights further study.
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Affiliation(s)
- Ping Liu
- School of Population Health, The University of Western Australia, M431, 35 Stirling Highway, Crawley, Perth, WA, 6009, Australia.
| | - Min Zhang
- School of Population Health, The University of Western Australia, M431, 35 Stirling Highway, Crawley, Perth, WA, 6009, Australia.,Center for Healthcare Resilience and Implementation Science, Australian Institute of Health Innovation, Macquarie University, Level 6, 75 Talavera Road, Sydney, NSW, 2109, Australia
| | - Xing Xie
- Women's Hospital, School of Medicine, Zhejiang University, 1 Xueshi Road, Hangzhou, 310006, Zhejiang, People's Republic of China
| | - Jie Jin
- Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, People's Republic of China
| | - C D'Arcy J Holman
- School of Population Health, The University of Western Australia, M431, 35 Stirling Highway, Crawley, Perth, WA, 6009, Australia
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Management of side effects in the personalized medicine era: chemotherapy-induced peripheral neuropathy. Methods Mol Biol 2015; 1175:301-22. [PMID: 25150874 DOI: 10.1007/978-1-4939-0956-8_12] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Pharmacogenomics has been establishing itself as a powerful tool to predict individual response to treatment, in order to personalize therapy management; this field has been explored in particular in Oncology. Not only efficacy on the malignant disease has been investigated, but also the possibility to predict adverse effects due to drug administration. Chemotherapy-Induced Neurotoxicity (CIPN) is one of those. This potentially severe and long-lasting/permanent side effect of commonly administered anticancer drugs can severely impair Quality of Life (QoL) in a large cohort of long survival patients. So far, a pharmacogenomics-based approach in CIPN regard has been quite delusive, making a methodological improvement warranted in this field of interest: even the most refined genetic analysis cannot be effective if not applied correctly. Here, we try to devise why it is so, suggesting how THE "bench-side" (Pharmacogenomics) might benefit from and should cooperate with THE "bed-side" (Clinimetrics), in order to make genetic profiling effective if applied to CIPN.
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Jensen NF, Stenvang J, Beck MK, Hanáková B, Belling KC, Do KN, Viuff B, Nygård SB, Gupta R, Rasmussen MH, Tarpgaard LS, Hansen TP, Budinská E, Pfeiffer P, Bosman F, Tejpar S, Roth A, Delorenzi M, Andersen CL, Rømer MU, Brünner N, Moreira JMA. Establishment and characterization of models of chemotherapy resistance in colorectal cancer: Towards a predictive signature of chemoresistance. Mol Oncol 2015; 9:1169-85. [PMID: 25759163 DOI: 10.1016/j.molonc.2015.02.008] [Citation(s) in RCA: 86] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Revised: 01/13/2015] [Accepted: 02/16/2015] [Indexed: 02/07/2023] Open
Abstract
Current standard treatments for metastatic colorectal cancer (CRC) are based on combination regimens with one of the two chemotherapeutic drugs, irinotecan or oxaliplatin. However, drug resistance frequently limits the clinical efficacy of these therapies. In order to gain new insights into mechanisms associated with chemoresistance, and departing from three distinct CRC cell models, we generated a panel of human colorectal cancer cell lines with acquired resistance to either oxaliplatin or irinotecan. We characterized the resistant cell line variants with regards to their drug resistance profile and transcriptome, and matched our results with datasets generated from relevant clinical material to derive putative resistance biomarkers. We found that the chemoresistant cell line variants had distinctive irinotecan- or oxaliplatin-specific resistance profiles, with non-reciprocal cross-resistance. Furthermore, we could identify several new, as well as some previously described, drug resistance-associated genes for each resistant cell line variant. Each chemoresistant cell line variant acquired a unique set of changes that may represent distinct functional subtypes of chemotherapy resistance. In addition, and given the potential implications for selection of subsequent treatment, we also performed an exploratory analysis, in relevant patient cohorts, of the predictive value of each of the specific genes identified in our cellular models.
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Affiliation(s)
- Niels F Jensen
- University of Copenhagen, Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Frederiksberg, Denmark
| | - Jan Stenvang
- University of Copenhagen, Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Frederiksberg, Denmark
| | - Mette K Beck
- Technical University of Denmark, Department for Systems Biology, Center for Biological Sequence Analysis, Lyngby, Denmark
| | - Barbora Hanáková
- Masaryk University, Faculty of Medicine, Institute of Biostatistics and Analyses, Brno, Czech Republic
| | - Kirstine C Belling
- Technical University of Denmark, Department for Systems Biology, Center for Biological Sequence Analysis, Lyngby, Denmark
| | - Khoa N Do
- Technical University of Denmark, Department for Systems Biology, Center for Biological Sequence Analysis, Lyngby, Denmark
| | - Birgitte Viuff
- University of Copenhagen, Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Frederiksberg, Denmark
| | - Sune B Nygård
- University of Copenhagen, Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Frederiksberg, Denmark
| | - Ramneek Gupta
- Technical University of Denmark, Department for Systems Biology, Center for Biological Sequence Analysis, Lyngby, Denmark
| | - Mads H Rasmussen
- Aarhus University Hospital, Department of Molecular Medicine, Aarhus, Denmark
| | - Line S Tarpgaard
- University of Southern Denmark, Institute of Clinical Research, Oncology Unit, Odense, Denmark
| | - Tine P Hansen
- University of Southern Denmark, Institute of Clinical Research, Pathology Unit, Odense, Denmark
| | - Eva Budinská
- Masaryk University, Faculty of Medicine, Institute of Biostatistics and Analyses, Brno, Czech Republic
| | - Per Pfeiffer
- University of Southern Denmark, Institute of Clinical Research, Oncology Unit, Odense, Denmark
| | - Fred Bosman
- University of Lausanne, University Institute of Pathology, Lausanne, Switzerland
| | - Sabine Tejpar
- University Hospital Gasthuisberg, Digestive Oncology Unit, Leuven, Belgium
| | - Arnaud Roth
- University Hospital of Geneva, Oncosurgery Unit, Geneva, Switzerland
| | - Mauro Delorenzi
- SIB Swiss Institute of Bioinformatics, Bioinformatics Core Facility, Lausanne, Switzerland; University of Lausanne, Ludwig Center for Cancer Research, Lausanne, Switzerland; University of Lausanne, Oncology Department, Lausanne, Switzerland
| | - Claus L Andersen
- Aarhus University Hospital, Department of Molecular Medicine, Aarhus, Denmark
| | - Maria U Rømer
- University of Copenhagen, Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Frederiksberg, Denmark
| | - Nils Brünner
- University of Copenhagen, Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Frederiksberg, Denmark.
| | - José M A Moreira
- University of Copenhagen, Faculty of Health and Medical Sciences, Department of Veterinary Disease Biology, Frederiksberg, Denmark
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Johnson C, Pankratz VS, Velazquez AI, Aakre JA, Loprinzi CL, Staff NP, Windebank AJ, Yang P. Candidate pathway-based genetic association study of platinum and platinum-taxane related toxicity in a cohort of primary lung cancer patients. J Neurol Sci 2015; 349:124-8. [PMID: 25586538 PMCID: PMC4334320 DOI: 10.1016/j.jns.2014.12.041] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Revised: 12/19/2014] [Accepted: 12/29/2014] [Indexed: 11/18/2022]
Abstract
BACKGROUND Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity secondary to chemotherapy. Genetic factors may be important in predisposing patients to this adverse effect. PATIENTS AND METHODS We studied 950 primary lung cancer patients, who received platinum or platinum-combination drug chemotherapy and who had DNA available for study. We analyzed epidemiological risk factors in 279 CIPN patients and 456 non-CIPN patients and genetic risk factors in 141 CIPN patients and 259 non-CIPN patients. The risk factors studied included demographic, diagnostic, and treatment data, as well as 174 tag SNPs (single nucleotide polymorphisms) across 43 candidate genes in the glutathione, cell cycle, DNA repair, cell signaling, and apoptosis pathways. RESULTS Patients who had diabetes mellitus were more likely to have CIPN (p=0.0002). Other epidemiologic risk factors associated with CIPN included number of cycles (p=0.0004) and type of concurrent chemotherapy (p<0.001). SNPs most associated with CIPN were in glutathione peroxidase 7 (GPX7) gene (p values 0.0015 and 0.0028, unadjusted and adjusted) and in ATP-binding cassette sub-family C member 4 (ABCC4) gene (p values 0.037 and 0.006, unadjusted and adjusted). We also found other suggestive associations in methyl-o-guanine-methyl-transferase (MGMT) and glutathione-S-transferase (GST) isoforms. CONCLUSIONS Epidemiological and genetic risk factors associated with CIPN in this cohort, included the type of chemotherapy drug, intensity of chemotherapy treatment, and genes known to be associated with chemotherapy resistance. These findings suggest that differentiating between cytotoxic and neurotoxic mechanisms of chemotherapy drugs is challenging but represents an important step toward individualized therapy and improving quality of life for patients.
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Affiliation(s)
- Cassandra Johnson
- Departments of Neurology, Oncology, Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Vernon S Pankratz
- Departments of Neurology, Oncology, Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Ana I Velazquez
- Departments of Neurology, Oncology, Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Jeremiah A Aakre
- Departments of Neurology, Oncology, Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Charles L Loprinzi
- Departments of Neurology, Oncology, Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Nathan P Staff
- Departments of Neurology, Oncology, Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Anthony J Windebank
- Departments of Neurology, Oncology, Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN, USA.
| | - Ping Yang
- Departments of Neurology, Oncology, Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN, USA
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Mohelnikova-Duchonova B, Melichar B, Soucek P. FOLFOX/FOLFIRI pharmacogenetics: The call for a personalized approach in colorectal cancer therapy. World J Gastroenterol 2014; 20:10316-10330. [PMID: 25132748 PMCID: PMC4130839 DOI: 10.3748/wjg.v20.i30.10316] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 03/05/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
While 5-fluorouracil used as single agent in patients with metastatic colorectal cancer has an objective response rate around 20%, the administration of combinations of irinotecan with 5-fluorouracil/folinic acid or oxaliplatin with 5-fluorouracil/folinic acid results in significantly increased response rates and improved survival. However, the side effects of systemic therapy such as myelotoxicity, neurotoxicity or gastrointestinal toxicity may lead to life-threatening complications and have a major impact on the quality of life of the patients. Therefore, biomarkers that would be instrumental in the choice of optimal type, combination and dose of drugs for an individual patient are urgently needed. The efficacy and toxicity of anticancer drugs in tumor cells is determined by the effective concentration in tumor cells, healthy tissues and by the presence and quantity of the drug targets. Enzymes active in drug metabolism and transport represent important determinants of the therapeutic outcome. The aim of this review was to summarize published data on associations of gene and protein expression, and genetic variability of putative biomarkers with response to therapy of colorectal cancer to 5-fluorouracil/leucovorin/oxaliplatin and 5-fluorouracil/leukovorin/irinotecan regimens. Gaps in the knowledge identified by this review may aid the design of future research and clinical trials.
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18
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Bai YL, Zhou B, Jing XY, Zhang B, Huo XQ, Ma C, He JM. Predictive role of GSTs on the prognosis of breast cancer patients with neoadjuvant chemotherapy. Asian Pac J Cancer Prev 2013; 13:5019-22. [PMID: 23244102 DOI: 10.7314/apjcp.2012.13.10.5019] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE To evaluate the predictive value of GST gene polymorphisms with regard to prognosis of breast cancer patients receiving neoadjuvant chemotherapy. METHODS A total of 159 patients were included in our study between January 2005 and January 2007. All the patients were followed up until January 2012. Genotyping was based upon the duplex polymerase-chain-reaction with the PCR-CTPP method. RESULTS Patients with null GSTM1 and GSTP1 Val/Val genotypes had significantly had better response rates to chemotherapy when compared with non-null GSTM1 and GSTP1 Ile/ Ile genotypes (OR=1.96 and OR=2.14, respectively). Patients with the GSTM1 null genotype had a longer average survival time and significantly lower risk of death than did those with non-null genotypes (HR=0.66). Similarly, those carrying the GSTP1 Val/Val genotype had 0.54- fold the risk of death of those with GSTP1 Ile/ Ile (HR=0.54). CONCLUSION A significant association was found between GSTM1 and GSTP1 gene polymorphisms and clinical outcomes in breast cancer cases.
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Affiliation(s)
- Yun-Lu Bai
- Department of Ultrasound, First Affiliated Hospital, Xinxiang Medical College, Xinxiang, China
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19
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Multidrug resistance in primary tumors and metastases in patients with esophageal squamous cell carcinoma. Pathol Oncol Res 2013; 19:641-8. [PMID: 23508648 DOI: 10.1007/s12253-013-9623-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Accepted: 03/05/2013] [Indexed: 01/05/2023]
Abstract
Studies have demonstrated that radical esophagectomy can significantly prolong disease-free survival and improve the survival rate of patients with T3 or T4 esophageal cancer and lymph node metastasis. Multidrug resistant cancer cells have active efflux mechanisms that prevent the accumulation of chemotherapeutic drugs in the cells. The purpose of this study was to compare the expression of five MDR related proteins between primary tumors in patients with thoracic esophageal squamous cell carcinoma (ESCC) and metastatic cancer in lymph nodes to explore the clinical significance of heterogeneity in MDR metastatic cancer cells. Fifty-four patients with ESCC and lymph node metastasis were included. All patients underwent subtotal esophagectomy and D2/D3 lymph node resection. The expression of lung resistance-related protein (LRP), P-glycoprotein, topoisomerase-II, thymidylate synthase, and glutathione S-transferase P1-1 (GST-π) were determined in the primary tumors and lymph nodes via immunohistochemistry. The expression of LRP was significantly different between the primary tumors and lymph nodes (P = 0.026). No significant differences were found for the other four proteins, and protein expression was not associated with either degree of differentiation or disease stage. It was also found that GST-π was expressed in all patients in both the primary tumors and lymph nodes, suggesting that the design and application of chemotherapeutic protocols capable of reducing GST-π expression may be beneficial for patients with ESCC. Additional research regarding the clinical utility of MDR protein expression in ESCC is warranted to design effective chemotherapeutic protocols.
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20
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Hassan M, Andersson BS. Role of pharmacogenetics in busulfan/cyclophosphamide conditioning therapy prior to hematopoietic stem cell transplantation. Pharmacogenomics 2013; 14:75-87. [PMID: 23252950 DOI: 10.2217/pgs.12.185] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Hematopoietic stem cell transplantation (HSCT) is a curative treatment for several malignant and nonmalignant disorders. Busulfan (Bu) and cyclophosphamide (Cy) are the most commonly used alkylators in high-dose pretransplant conditioning for HSCT; a treatment that is correlated with drug-related toxicity and relapse. Pharmacogenetic investigations have shown that CYP450, as well as aldehyde dehydrogenase, are clearly involved with Cy metabolism and are associated with altered treatment response, Cy metabolism and the unique stem-cell sparing capacity. Moreover, glutathione-S-transferase isoenzymes have been associated with cellular outward transport of various alkylating agents, including Cy metabolites, melphalan, Bu and chlorambucil. A shift from genetic-based studies to whole-genome-based investigations of Cy- and Bu-associated markers may contribute to personalizing the conditioning therapy and enhancing the clinical outcome of HSCT.
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Affiliation(s)
- Moustapha Hassan
- Experimental Cancer Medicine (ECM), Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
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Jankova L, Robertson G, Chan C, Tan KL, Kohonen-Corish M, Fung CLS, Clarke C, Lin BPC, Molloy M, Chapuis PH, Bokey L, Dent OF, Clarke SJ. Glutathione S-transferase Pi expression predicts response to adjuvant chemotherapy for stage C colon cancer: a matched historical control study. BMC Cancer 2012; 12:196. [PMID: 22639861 PMCID: PMC3420323 DOI: 10.1186/1471-2407-12-196] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2011] [Accepted: 05/11/2012] [Indexed: 01/19/2023] Open
Abstract
Background This study examined the association between overall survival and Glutathione S-transferase Pi (GST Pi) expression and genetic polymorphism in stage C colon cancer patients after resection alone versus resection plus 5-fluourouracil-based adjuvant chemotherapy. Methods Patients were drawn from a hospital registry of colorectal cancer resections. Those receiving chemotherapy after it was introduced in 1992 were compared with an age and sex matched control group from the preceding period. GST Pi expression was assessed by immunohistochemistry. Overall survival was analysed by the Kaplan-Meier method and Cox regression. Results From an initial 104 patients treated with chemotherapy and 104 matched controls, 26 were excluded because of non-informative immunohistochemistry, leaving 95 in the treated group and 87 controls. Survival did not differ significantly among patients with low GST Pi who did or did not receive chemotherapy and those with high GST Pi who received chemotherapy (lowest pair-wise p = 0.11) whereas patients with high GST Pi who did not receive chemotherapy experienced markedly poorer survival than any of the other three groups (all pair-wise p <0.01). This result was unaffected by GST Pi genotype. Conclusion Stage C colon cancer patients with low GST Pi did not benefit from 5-fluourouracil-based adjuvant chemotherapy whereas those with high GST Pi did.
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Affiliation(s)
- Lucy Jankova
- Cancer Pharmacology Unit, ANZAC Research Institute, Concord Hospital, The University of Sydney, Sydney, NSW 2139, Australia
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Benhaim L, Labonte MJ, Lenz HJ. Pharmacogenomics and metastatic colorectal cancer: current knowledge and perspectives. Scand J Gastroenterol 2012; 47:325-39. [PMID: 22182673 DOI: 10.3109/00365521.2012.640832] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The pharmacogenomics field is crucial for optimizing the selection of which chemotherapy regimen to use according to the patient's genomic profile. Indeed, the individual's inherited genome accounts for a large proportion of the variation in his or her response to chemotherapeutic agents both in terms of efficiency and toxicity. Patients with metastatic disease are more likely to receive different lines of chemotherapy with variable efficacy and experience some related complications. It is therefore critical to tailor the best therapeutic arsenal to improve the efficacy and avoid as much as possible related complications that are susceptible to interrupt the treatment. The pharmacogenomics approach investigates for each drug the implicated metabolic pathway and the potential personal variations in gene function. The aim of this review is to present a clear overview of the most accurate polymorphisms that have been identified as related to drug response in patients with mCRC.
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Affiliation(s)
- Leonor Benhaim
- Division of Medical Oncology, USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
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Drobná Z, Del Razo LM, Garcia-Vargas G, Sánchez-Ramírez B, González-Horta C, Ballinas-Casarrubias L, Loomis D, Stýblo M. Identification of the GST-T1 and GST-M1 null genotypes using high resolution melting analysis. Chem Res Toxicol 2011; 25:216-24. [PMID: 22136492 DOI: 10.1021/tx200457u] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Glutathione S-transferases, including GST-T1 and GST-M1, are known to be involved in the phase II detoxification pathways for xenobiotics as well as in the metabolism of endogenous compounds. Polymorphisms in these genes have been linked to an increased susceptibility to carcinogenesis and associated with risk factors that predispose to certain inflammatory diseases. In addition, GST-T1 and GST-M1 null genotypes have been shown to be responsible for interindividual variations in the metabolism of arsenic, a known human carcinogen. To assess the specific GST genotypes in the Mexican population chronically exposed to arsenic, we have developed a multiplex High Resolution Melting PCR (HRM-PCR) analysis using a LightCycler480 instrument. This method is based on analysis of the PCR product melting curve that discriminates PCR products according to their lengths and base sequences. Three pairs of primers that specifically recognize GST-T1, GST-M1, and β-globin, an internal control, to produce amplicons of different length were designed and combined with LightCycler480 High Resolution Melting Master Mix containing ResoLight, a completely saturating DNA dye. Data collected from melting curve analysis were evaluated using LightCycler480 software to determine specific melting temperatures of individual melting curves representing target genes. Using this newly developed multiplex HRM-PCR analysis, we evaluated GST-T1 and GST-M1 genotypes in 504 DNA samples isolated from the blood of individuals residing in Zimapan, Lagunera, and Chihuahua regions in Mexico. We found that the Zimapan and Lagunera populations have similar GST-T1 and GST-M1 genotype frequencies which differ from those of the Chihuahua population. In addition, 14 individuals have been identified as carriers of the double null genotype, i.e., null genotypes in both GST-T1 and GST-M1 genes. Although this procedure does not distinguish between biallelic (+/+) and monoallelic (+/-) genotypes, it can be used in an automated workflow as a simple, sensitive, and time and money saving procedure for rapid identification of the GST-T1 and GST-M1 positive or null genotypes.
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Affiliation(s)
- Zuzana Drobná
- Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, North Carolina 27599-7461, United States.
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Li W, Yue W, Yang X, Zhang C, Wang Y. [Relationship between the genetic polymorphisms of phase I and II drug-metabolizing enzymes, as well as the outcome of chemotherapy in advanced non-small cell lung cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2011; 14:858-64. [PMID: 22104220 PMCID: PMC5999999 DOI: 10.3779/j.issn.1009-3419.2011.11.05] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
背景与目的 目前药物代谢酶遗传多态性与化疗疗效关系的研究结果多不一致，本研究旨在探讨细胞色素P4501A1（cytochrome P450 1A1, CYP1A1）、2E1（cytochrome P450 2E1, CYP2E1）、2D6（cytochrome P450 2D6, CYP2D6）和谷胱甘肽硫转移酶M1（glutathione S-transferase M1, GSTM1）基因多态性与晚期非小细胞肺癌化疗疗效以及与肺癌患者预后的关系。 方法 采用PCR和PCR-RFLP技术对肺癌患者4种药物代谢酶基因分型，并对他们进行5年跟踪随访。 结果 携带B型CYP1A1和缺陷性GSTM1肺癌患者比其它基因型患者化疗疗效好（P < 0.001）。携带A型CYP1A1肺癌患者接受非铂类化疗药物治疗比B型和C型患者疗效好（P=0.041）; 携带缺陷性GSTM1肺癌患者接受铂类化疗药物治疗疗效比功能型患者疗效好（P=0.011）。4种酶对晚期非小细胞肺癌患者总生存期（overall survival, OS）没有明显影响（P > 0.05）。 结论 A型CYP1A1肺癌患者接受非铂类化疗药物治疗比B型和C型患者疗效好; 缺陷性GSTM1肺癌患者接受铂类化疗药物治疗比功能型患者疗效好。4种酶基因多态对晚期非小细胞肺癌患者OS影响没有明显统计学差异。
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Affiliation(s)
- Weiying Li
- Department of Cell Molecular Biology, Beijing Thoracic Tumour and Tuberculosis Research Institute, Beijing 101149, China.
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Polymorphisms in GSTM1, CYP1A1, CYP2E1, and CYP2D6 are associated with susceptibility and chemotherapy response in non-small-cell lung cancer patients. Lung 2011; 190:91-8. [PMID: 22109568 DOI: 10.1007/s00408-011-9338-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2011] [Accepted: 09/29/2011] [Indexed: 10/15/2022]
Abstract
BACKGROUND Studies of polymorphisms in CYP1A1, CYP2E1, CYP2D6, and GSTM1 and their relationship to lung cancer susceptibility and chemotherapy response have been reported, but the results are not consistent. In this study we selected four polymorphisms in these genes, several of which have previously been researched, and investigated their association with lung cancer susceptibility and chemotherapy response. METHODS We genotyped the four polymorphisms in a cohort composed of 217 non-small-cell lung cancer (NSCLC) patients and 198 controls. Of these, 145 advanced NSCLC patients underwent chemotherapy and were monitored for 5 years. RESULTS Significant differences in the GSTM1 polymorphism were observed between the case and control groups (P = 0.02). We observed a synergistic effect of smoking and GSTM1. Smokers with deficient-type GSTM1 had a 4.96-fold increased risk of developing lung cancer. Significant differences in GSTM1 and CYP1A1 polymorphisms were observed between the response and nonresponse groups (P = 0.004 and P = 0.026). Moreover, patients with deficient-type GSTM1 were superior responders to platinum drugs than those carrying wild-type GSTM1 (P = 0.014). In addition, patients carrying TT CYP1A1 responded better to nonplatinum drugs than those carrying TC and CC CYP1A1 (P = 0.01). Polymorphisms in the four enzymes had no effect on the overall survival of NSCLC patients. CONCLUSIONS Our findings support the hypothesis that a polymorphism in GSTM1 is associated with lung cancer susceptibility. Furthermore, polymorphisms in GSTM1 and CYP1A1 were associated with chemotherapy response. In particular, smokers carrying deficient-type GSTM1 were at a higher risk of developing lung cancer. Patients carrying deficient-type GSTM1 responded better to platinum drugs, while those with TT CYP1A1 were better responders to nonplatinum drugs.
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Abstract
Colorectal cancer (CRC) has been re-classified based on molecular analyses of various genes and proteins capable of separating morphologic types of tumors into molecular categories. The diagnosis and management of CRC has evolved with the discovery and validation of a wide variety of biomarkers designed to facilitate a personalized approach for the treatment of the disease. In addition, a number of new prognostic and predictive individual genes and proteins have been discovered that are designed to reflect the sensitivity and/or resistance of CRC to existing therapies. Multigene predictors have also been developed to predict the risk of relapse for intermediate-stage CRC after completion of surgical resection. Finally, a number of biomarkers have been proposed as specific predictors of chemotherapy and radiotherapy response and, in some instances, drug toxicity. In this article, a series of novel biomarkers are considered and compared with standard-of-care markers for their potential use as pharmacogenomic and pharmacogenetic predictors of disease outcome.
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Cavaletti G, Alberti P, Marmiroli P. Chemotherapy-induced peripheral neurotoxicity in the era of pharmacogenomics. Lancet Oncol 2011; 12:1151-61. [PMID: 21719347 DOI: 10.1016/s1470-2045(11)70131-0] [Citation(s) in RCA: 93] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Development of advanced and high-throughput methods to study variability in human genes means we can now use pharmacogenomic analysis not only to predict response to treatment but also to assess the toxic action of drugs on normal cells (so-called toxicogenomics). This technological progress could enable us to identify individuals at high and low risk for a given side-effect. Pharmacogenomics could be very useful for stratification of cancer patients at risk of developing chemotherapy-induced peripheral neurotoxicity, one of the most severe and potentially permanent non-haematological side-effects of modern chemotherapeutic agents. However, study data reported so far are inconsistent, which suggests that methodological improvement is needed in clinical trials to obtain reliable results in this clinically relevant area.
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Affiliation(s)
- Guido Cavaletti
- Department of Neuroscience and Biomedical Technologies, University of Milano-Bicocca, Monza, Italy.
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Deenen MJ, Cats A, Beijnen JH, Schellens JHM. Part 3: Pharmacogenetic variability in phase II anticancer drug metabolism. Oncologist 2011; 16:992-1005. [PMID: 21659608 DOI: 10.1634/theoncologist.2010-0260] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Equivalent drug doses may lead to wide interpatient variability in drug response to anticancer therapy. Known determinants that may affect the pharmacological response to a drug are, among others, nongenetic factors, including age, gender, use of comedication, and liver and renal function. Nonetheless, these covariates do not explain all the observed interpatient variability. Differences in genetic constitution among patients have been identified to be important factors that contribute to differences in drug response. Because genetic polymorphism may affect the expression and activity of proteins encoded, it is a key covariate that is responsible for variability in drug metabolism, drug transport, and pharmacodynamic drug effects. We present a series of four reviews about pharmacogenetic variability. This third part in the series of reviews is focused on genetic variability in phase II drug-metabolizing enzymes (glutathione S-transferases, uridine diphosphoglucuronosyl transferases, methyltransferases, sulfotransferases, and N-acetyltransferases) and discusses the effects of genetic polymorphism within the genes encoding these enzymes on anticancer drug therapy outcome. Based on the literature reviewed, opportunities for patient-tailored anticancer therapy are proposed.
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Affiliation(s)
- Maarten J Deenen
- The Netherlands Cancer Institute, Department of Medical Oncology, Amsterdam, The Netherlands
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Ross JS, Torres-Mora J, Wagle N, Jennings TA, Jones DM. Biomarker-based prediction of response to therapy for colorectal cancer: current perspective. Am J Clin Pathol 2010; 134:478-90. [PMID: 20716806 DOI: 10.1309/ajcp2y8ktdpoaorh] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The diagnosis and management of colorectal cancer (CRC) has been impacted by the discovery and validation of a wide variety of biomarkers designed to facilitate a personalized approach for the treatment of the disease. Recently, CRC has been reclassified based on molecular analyses of various genes and proteins capable of separating morphologic types of tumors into molecular categories. At the same time, a number of new prognostic and predictive single genes and proteins have been discovered that are designed to reflect sensitivity and/or resistance to existing therapies. Multigene predictors have also been developed to predict the risk of relapse for intermediate-stage CRC after completion of surgical extirpation. More recently, a number of biomarkers tested by a variety of methods have been proposed as specific predictors of chemotherapy and radiotherapy response. Other markers have been successfully used to predict toxic effects of standard therapies. In this review, a series of novel biomarkers are considered and compared with standard-of-care markers for their potential use as pharmacogenomic and pharmacogenetic predictors of disease outcome.
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