Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy

Pullarkat, Sheeja T.; Stoehlmacher, Jan; Ghaderi, Viviane S.; Xiong, Yi; Ingles, Sue A.; Sherrod, Andy; Warren, Robert S.; Tsao-Wei, Denise D.; Groshen, Susan; Lenz, Heinz‐Josef

doi:10.1038/sj.tpj.6500012

Cited by 530 publications

(355 citation statements)

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“…DISCUSSION A number of retrospective studies have demonstrated that the TS expression is influenced by the VNTR located in the promoter of the TS gene. Pullarkat et al 26 found a 3.6-fold increase in TS mRNA levels in individuals homozygous for TS*3 compared to TS*2 homozygotes (p ϭ 0.004) and a 1.7-fold increase in patients homozygous for TS*3 with respect to patients heterozygous TS*2/ TS*3 (p ϭ 0.05). Their study also showed that, in 50 patients receiving 5-FU for metastatic colorectal cancer, there was a higher response rate in patients with low numbers of TS repeats (50% for *2/*2, 15% for *2/*3 and 9% for *3/*3).…”

Section: Correlation Between Ts Genotype and Outcome Of Chemotherapymentioning

confidence: 97%

“…Patients with *2/*2 genotype have a good prognosis, but patients with *3/*2 genotype are sometimes included in the good prognosis group 27 and other times in the intermediate or bad prognosis group. 12,26 In a recent work, Uchida et al 29 reported that the loss of heterozygosity at the TS locus in tumor samples of colorectal cancer patients treated with fluoropyrimidine therapy affects tumor response and survival in those patients with a heterozygous TS*2/*3 genotype. In 17 of 22 of these heterozygous cases, a LOH was demonstrated in tumor tissues The authors reported that the response rate of the TS*2/loss tumor genotype patients was 80% and that only 1 of 7 tumors with a genotype of *3/loss showed a response.…”

Section: Correlation Between Ts Genotype and Survivalmentioning

confidence: 99%

See 1 more Smart Citation

Single nucleotide polymorphism in the 5′ tandem repeat sequences of thymidylate synthase gene predicts for response to fluorouracil‐based chemotherapy in advanced colorectal cancer patients

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Río

et al. 2004

Intl Journal of Cancer

132

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Thymidylate synthase (TS) is the primary target of 5-fluorouracil (5-FU).A VNTR polymorphism in the TS promoter region is associated with the efficacy of 5-FU-based chemotherapy in colorectal cancer. A common G>C SNP at the 12th nucleotide of the second repeat in the TS*3 alleles has been recently described. The combination of SNP and VNTR allows the definition of 3 TS alleles: *2, *3G and *3C. The aim of our study was to evaluate the predictive value of clinical response and survival of these new defined TS alleles. TS genotypes of 89 patients diagnosed with metastatic colorectal cancer and undergoing 5-FU-based chemotherapy were carried out. The clinical outcome was evaluated according to the genotype (high expression genotype: *2R/*3G; *3C/*3G; *3G/*3G; and low expression genotype: *2R/*2R; *2R/*3C; *3C/*3C. A higher overall response was observed in the group of patients with a low expression genotype (p ‫؍‬ 0.035). The probability of achieving a clinical response of patients with a low expression-related genotype was 2.9 higher than that of the other group (95% CI ‫؍‬ 1.03-5.6, p ‫؍‬ 0.04). The median time to progression was 12 months and 9 months in the low and high expression groups, respectively (p ‫؍‬ 0.07, log rank test). Overall survival was significantly longer in the low expression group. In this group the median OS was not achieved at 50 months of follow-up in contrast to the 20 months observed in the high expression group (p ‫؍‬ 0.03). TS genotype was an independent predictor of progression-free and overall survival in the Cox regression models after adjustment to the other clinical variables. The selection of patients who are likely to respond to 5-FU therapy may be considerably improved if the TS genotype were to include both the VNTR and the SNP located within the promoter region of the gene. © 2004 Wiley-Liss, Inc. Key words: 5-FU resistance; TS-polymorphism; colorectal cancer; fluoropyrimidine chemotherapyA high proportion of colorectal cancer, which is a leading cause of cancer-related morbidity and mortality in the Western world, is diagnosed at advanced stages when chemotherapy is required for its management. 5-Fluorouracil (5-FU) is a folate-pathway inhibitor that has been available for 50 years, and continues to be a mainstay of treatment of advanced disease. 1 This drug is a fluoropyrimidine that, on activation to the nucleotide form, develops a stable complex with thymidylate synthase (TS), inhibiting the activity of the enzyme. 2 TS catalyzes the reductive methylation of dUMP by 5,10-methylenetetrahydrofolate to form dTNP, which is a critical reaction for cell proliferation. 3 Early in vitro studies have demonstrated more resistance to 5-FU of cell lines with high TS expression 4 or transfected with wild-type TS cDNA. 5 A number of studies have been published indicating that patients with high tumor levels of TS are unlikely to respond to infusion treatment with 5-FU, whereas patients with low levels have response rates that are higher than expected. 6 -13 The agreement between these...

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Section: Correlation Between Ts Genotype and Outcome Of Chemotherapymentioning

confidence: 97%

Section: Correlation Between Ts Genotype and Survivalmentioning

confidence: 99%

Single nucleotide polymorphism in the 5′ tandem repeat sequences of thymidylate synthase gene predicts for response to fluorouracil‐based chemotherapy in advanced colorectal cancer patients

Marcuello

Altés

Río

et al. 2004

Intl Journal of Cancer

132

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“…43 In general, most published data support that patients with metastatic disease and low TS expression showed a trend toward better response to chemotherapy and longer survival, but possibly more severe toxicities, than did the high TS expression counterpart genotypes (for example, 3R/ 3R, þ 6 bp/ þ 6 bp), both in the adjuvant and advanced settings. 34,44,45 This trend was confirmed in a meta-analysis reviewing the association of TS expression and prognosis in advanced and localized CRC, but there was evidence of heterogeneity and possible publication bias. 46 Therefore, TS was not recommended as a prognostic or predictive tumor marker by the American Society of Clinical Oncology in the 2006 Update of Recommendations for the Use of Tumor Markers in Gastrointestinal Cancer.…”

Section: Cytotoxics: Pharmacogenetics and Molecular Markersmentioning

confidence: 86%

“…34,35 In contrast, 2R/ 2R genotype has been associated with low levels of TS expression and better clinical outcome to therapy. 35,36 In addition to the above genotypic groups, a single-nucleotide polymorphism (SNP; G-C), observed at the 12th position of the second repeat of the 3R allele, at its upstream stimulatory factor family E-box elements, reduces its translational activity and causes low TS expression and therefore an altered outcome similar to 2R.…”

Section: Cytotoxics: Pharmacogenetics and Molecular Markersmentioning

confidence: 99%

Pharmacogenetics and biomarkers in colorectal cancer

2009

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The prognosis of patients with colorectal cancer (CRC) is affected by various factors at the time of diagnosis, including location of the tumor, gender, age and overall performance status of the patient. Predicting response and limiting drug-induced toxicity for patients with CRC are also critical. Interpatient differences in tumor response and drug toxicity are common during chemotherapy. Genomic variability of key metabolic enzyme complexes, drug targets and drug transport molecules are important contributing factors. At present, there is inconsistent and rather low use of pharmacogenetic testing in the clinical setting because of a lack of robust evidence or of resources. Patients' selection and tailored treatments by the introduction of genetic testing will hopefully allow better response prediction and limit drug-induced toxicity leading to improved patient outcomes in the most cost-effective way. Here, we review the main genetic alterations observed in familial and sporadic CRC and their associations with the metabolism, efficacy and toxicities of drugs used in this disease.

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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%

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 gene polymorphism determines response and toxicity of 5-FU chemotherapy

Cited by 530 publications

References 18 publications

Single nucleotide polymorphism in the 5′ tandem repeat sequences of thymidylate synthase gene predicts for response to fluorouracil‐based chemotherapy in advanced colorectal cancer patients

Single nucleotide polymorphism in the 5′ tandem repeat sequences of thymidylate synthase gene predicts for response to fluorouracil‐based chemotherapy in advanced colorectal cancer patients

Pharmacogenetics and biomarkers in colorectal cancer

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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