<i>Thymidylate Synthase</i> and <i>Methylenetetrahydrofolate Reductase</i> Gene Polymorphism in Normal Tissue As Predictors of Fluorouracil Sensitivity

Jakobsen, Anders; Nielsen, Joachim; Gyldenkerne, Niels; Lindeberg, Jan

doi:10.1200/jco.2005.06.219

Cited by 186 publications

(131 citation statements)

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“…We noticed that patients with a variant allele had a worse TRG. MTHFR-677TT genotype, causing an increased availability of folate intermediates, was expected to enhance patients responsiveness to 5-FU 31,32 though the influence of the polymorphism on the 5-FU pharmacological action is still Genetic polymorphisms predict response in rectal cancer controversial. 18,33 We could hypothesize an opposite role of the polymorphism on the RT efficacy because of MTHFR critical role in DNA synthesis and repair.…”

Section: Discussionmentioning

confidence: 99%

Tumor response is predicted by patient genetic profile in rectal cancer patients treated with neo-adjuvant chemo-radiotherapy

et al. 2010

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The aim of the study was the identification of a pharmacogenetic profile predictive of the tumor regression grade (TRG), considered as tumor response parameter, after neo-adjuvant treatment in rectal cancer patients. A total of 238 rectal cancer patients treated in a neo-adjuvant setting by a fluoropyrimidines-based chemo-radiotherapy (RT) were genotyped for 25 genetic polymorphisms in 16 genes relevant for treatment-associated pathways. Two polymorphisms were associated with TRG in a multivariate analysis: hOGG1-1245C4G, which can affect radiosensitivity and MTHFR-677C4T, which is involved in fluoropyrimidines action. Patients bearing at least one variant allele had a lower chance to get TRGp2 (OR ¼ 0.46 95% CI 0.23-0.90, P ¼ 0.024; and OR ¼ 0.48 95% CI 0.24-0.96, P ¼ 0.034; respectively). An association trend was observed for ABCB1-3435C4T, which is responsible for the multi-drug resistance (odds ratio (OR) ¼ 1.96, 95% confidence interval (CI) 0.98-3.95, P ¼ 0.057). Exploratory classification and regression tree (CART) analysis highlighted high-order gene-gene and gene-environment interactions and a genetic signature associated with differential response, with hOGG1-1245C4G as the most predictive factor. Other significant variables were: ABCB1-3435C4T, MTHFR-677C4T, ERCC1-8092C4A, ABCC2-1249G4A, XRCC1-28152G4A, XRCC3-4541A4G and patients gender. On the basis of CART results, patients were categorized into three groups according to tumor response probability: intermediate and high profiles had a higher probability to get TRGp2 as compared with low profiles (OR ¼ 4.12 95% CI 1. Po0.001 and OR ¼ 12.44, Po0.0001, respectively). This study evidences a major role of hOGG1-1245C4G and MTHFR-677C4T polymorphisms in the tumor response of rectal cancer patients treated with chemo-RT in neo-adjuvant setting, and shows the relevance of gene-gene and gene-environment interactions for complex phenotypes as tumor response.

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Section: Discussionmentioning

confidence: 99%

Tumor response is predicted by patient genetic profile in rectal cancer patients treated with neo-adjuvant chemo-radiotherapy

et al. 2010

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“…Therefore, the TS functional polymorphisms are under investigation for the possibility of optimising chemotherapy (Yong and Innocenti, 2007). Studies in patients with metastatic colorectal cancer showed that carriers of the TS 5 0 -UTR 3R (3G) and/or the TS 3 0 -UTR 6 þ alleles had adverse clinical outcomes (Pullarkat et al, 2001;Etienne et al, 2002;Park et al, 2002;Marcuello et al, 2004;Stoehlmacher et al, 2004;Martinez-Balibrea et al, 2007); however, such an association was not always detected (Lecomte et al, 2004;Jakobsen et al, 2005;Ruzzo et al, 2007a, b). Heterogeneity in clinical experimental conditions (Sorbye et al, 2007), in tumour burden (Köhne et al, 2002) and in genetic/molecular features in the presence of a multisite metastatic disease (Yokota, 2000) may explain variable results in these pharmacogenetic studies.…”

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confidence: 99%

Liver-only metastatic colorectal cancer patients and thymidylate synthase polymorphisms for predicting response to 5-fluorouracil-based chemotherapy

et al. 2008

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We investigated the association between thymidylate synthase (TS) germline polymorphisms and response to 5-fluorouracil-based chemotherapy in 80 patients with liver-only metastatic colorectal cancer (MCRC). The tandem repeat polymorphism (VNTR) in TS 5 0 -untranslated region (5 0 -UTR), which consists of two (2R) or three (3R) 28-bp repeated sequences, with or without a G/C nucleotide change in 3R carriers (3G or 3C) and a 6-bp insertion/deletion (6 þ /6À) in the TS 3 0 -UTR, was studied. The distinction between high (2R/3G, 3C/3G and 3G/3G) and low (2R/2R, 2R/3C and 3C/3C) TS expression genotypes according to the 5 0 -UTR VNTR þ G/C nucleotide change showed significant association with tumour response (P ¼ 0.01). In particular, high TS expression genotypes were found in 8 out of 34 patients (23.5%) with complete or partial response and in 24 out of 46 patients (52%) with stable disease and disease progression. Liver-only MCRC patients are a homogeneous and clinical relevant subgroup that may represent an ideal setting for studying the actual influence of TS polymorphisms.

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“…An association between the genotype of the TS enhancer region and response and toxicity with 5-FU-based therapy in patients with colorectal cancer has been reported previously. [29][30][31][32][33][34][35][36][37][38][39] : patients who are homozygous for the double-tandem repeat have a lower TS protein content and a higher likelihood of response, but a greater risk of toxicity. MTHFR is involved in the regeneration of 5 methyltetrahydrofolate from 5,10 methylenetetrahydrofolate.…”

Section: Discussionmentioning

confidence: 99%

“…MTHFR deficiency is the most common inherited folate metabolism disorder. 24,25,29,30 The wild-type CC at codon 667 is associated with normal activity of MTHFR. The C667T polymorphism is observed in approximately 40% of subjects, and results in an approximately 40% decrease in the activity of MTHFR.…”

Section: Discussionmentioning

confidence: 99%

A phase 1 clinical trial of sequential pralatrexate followed by a 48‐hour infusion of 5‐fluorouracil given every other week in adult patients with solid tumors

Grem

Kos

Evande

et al. 2015

Cancer

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BACKGROUND: Pralatrexate (PDX) is an inhibitor of dihydrofolate reductase that was rationally designed to improve cellular uptake and retention of the drug. Preclinical data have shown synergy with the sequential administration of a dihydrofolate reductase inhibitor followed 24 hours later by 5-fluorouracil (5-FU). METHODS: Twenty-seven patients were enrolled at 1 of 5 PDX dose levels from 75 to 185 mg/m 2 on day 1 followed 24 hours later by 5-FU at a dose of 3000 mg/m 2 /48 hours every 2 weeks with folic acid and vitamin B12 supplementation. Baseline blood was collected for pharmacogenetic analysis of polymorphisms of methylenetetrahydrofolate reductase and thymidylate synthase. RESULTS: Mucositis was the most common dose-limiting toxicity. When the worst toxicities across all cycles were considered, grade 3 to 4 neutropenia, anemia, and thrombocytopenia were found to have occurred in 14.8%, 14.8%, and 0% of patients, respectively. Grade 2 to 3 toxicities included mucositis (66.6%), dehydration (33.3%), fatigue (25.9%), and diarrhea (22.2%). Version 3.0 of the National Cancer Institute Common Toxicity Criteria was used to grade toxicities The median progression-free survival (PFS) was 112 days (range, 28-588 days). Seven patients (26%) had a PFS of >180 days (5 patients with colorectal cancer, 1 patient with pancreatic cancer, and 1 patient with non-small cell lung cancer). Polymorphisms in methylenetetrahydrofolate reductase and thymidylate synthase did not correlate with toxicity. CONCLUSIONS: The recommended dose of PDX was 148 mg/m 2 . A subset of heavily pretreated patients had PFS durations of 6 months with this regimen. Cancer 2015;121:3862-8. INTRODUCTION 5-fluorouracil (5-FU) and folate inhibitors of dihydrofolate reductase (DHFR), including methotrexate (MTX), are active in a variety of malignancies. There is strong preclinical evidence that the optimal sequence for combining DHFR inhibitors with 5-FU involves pretreatment with the DHFR inhibitor followed by 5-FU. 1-4 Administration of 5-FU followed by MTX is antagonistic in both in vitro and in vivo studies. The antipurine action of MTX is believed to result from 2 factors: 1) partial depletion of 10-formyl-tetrahydrofolate, which is required for purine synthesis; and 2) buildup of dihydrofolate, which is an inhibitor of de novo purine synthesis. Ongoing thymidylate synthesis is required to deplete the cellular reduced-folate pool. Pretreatment with 5-FU inhibits thymidylate synthase (TS) thereby blocking the conversion of reduced folates to dihydrofolate. The reduced-folate pool is thus spared for purine synthesis, and the dihydrofolate pool does not expand. When MTX precedes 5-FU, ongoing thymidylate synthesis depletes reduced folates and dihydrofolate pools accumulate, thus allowing blockade of purine biosynthesis. Inhibition of de novo purine synthesis expands the intracellular pool of phosphoribosyl pyrophosphate, which is then available for the anabolism of 5-FU to fluorouridine monophosphate by orotate phosphoribosyl transferase. Enhancement o...

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Thymidylate Synthase and Methylenetetrahydrofolate Reductase Gene Polymorphism in Normal Tissue As Predictors of Fluorouracil Sensitivity

Abstract: The analysis of gene polymorphism allows delineation of a group of patients (30%) with a response rate to a single drug of approximately 50%. This information should be used in the design of tailored treatment.

Cited by 186 publications

References 15 publications

Tumor response is predicted by patient genetic profile in rectal cancer patients treated with neo-adjuvant chemo-radiotherapy

Tumor response is predicted by patient genetic profile in rectal cancer patients treated with neo-adjuvant chemo-radiotherapy

Liver-only metastatic colorectal cancer patients and thymidylate synthase polymorphisms for predicting response to 5-fluorouracil-based chemotherapy

A phase 1 clinical trial of sequential pralatrexate followed by a 48‐hour infusion of 5‐fluorouracil given every other week in adult patients with solid tumors

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