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Pharmacogenetics of Colon Cancer and Potential Implications for 5- Fluorouracil-Based Chemotherapy

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The antimetabolite 5-fluorouracil (5-FU) is widely used in combination treatment of patients with advanced stages of colorectal cancer. In the last decade, several studies focused on genetically determined variability in function of certain enzymes that are involved in the metabolism of 5-fluoropyrimidines. Polymorphisms and mutations within the thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR) and dihydropyrimidine dehydrogenase (DPD) genes have been associated with response to or toxicity from treatment with 5-FU. Pharmacogenetic studies could therefore identify genetic markers that can be used to guide the treatment for each individual patient. However, the predictive role of these genetic markers is not straightforward. Controversial data have been found for polymorphisms in the TS gene. Similarly, the role of MTHFR is not clear. Mutations in the DPD gene seem more suitable to predict toxicity in part of the cases but seems less suitable for prediction of response. These inconsistencies across the literature regarding the impact of identified TS, MTHFR and DPD polymorphisms on enzyme levels and response to 5-FU-based drugs will be discussed in this review. More comprehensive genetic evaluation by combined analysis of several parameters is needed. To achieve this novel approaches such as expression array and array-CGH offer the best perspective.

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Keywords: Methylenetetrahydrofolate reductase (MTHFR); TS enhancer region (TSER); leucovorin; polymorphisms; single nucleotide polymorphism

Document Type: Research Article

Affiliations: Department of Medical Oncology, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.

Publication date: March 1, 2006

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  • Current Pharmacogenomics provides comprehensive overviews of all current research on pharmacogenomics and pharmacogenetics. All areas of the field from pre-clinical to clinical research are covered, including related areas such as genomics, proteomics, target discovery, bioinformatics and novel diagnostics. This international journal is peer-reviewed and publishes both mini- and full review articles.

    The journal has become essential reading for all researchers and clinicians with interests in pharmacogenomics and pharmacogenetics.
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