Artikel
Pharmacogenetics in colorectal cancer: a systematic review
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Autoren
Veröffentlicht: | 6. September 2007 |
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Gliederung
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Background and Objective: Pharmacological treatment in addition to surgical resection of colorectal cancer patients has reduced morbidity and increased survival rates over the past fifty years. There is however variability in treatment outcome for the multiple chemotherapeutic regimens employed. Therefore, individual treatment accounting for variability in the metabolism of therapeutic agents could enhance efficacy and minimize toxicity.
In this review, we briefly discuss the metabolic pathways of commonly used drugs or drug combinations for treatment of colorectal cancer and present known genetic variants that may impact these pathways. We give a structured overview of studies that have evaluated genetic variants with possible impact on treatment outcome and toxicity in colorectal cancer patients.
Methods: MEDLINE database and references in corresponding articles were searched for relevant articles published until March 2007. Details on patient selection, treatment regimens, genotype information, treatment outcome and toxicity were taken into account.
Results: Overall, 47 studies, including 34 retrospective and 13 prospective studies, were identified. Five different drugs used as basic treatment were considered.
By far the most extensively studied gene has been thymidylate synthase (TS). Most studies concerning TS as a target in 5-fluorouracil treatment have shown that those genotypes predicting a longer survival were also related to an increased risk of toxicity. Polymorphisms in glutathione-S-transferases that reduce enzyme detoxification activity of oxaliplatin have been associated with longer survival and increased toxicity. Polymorphisms in further genes, such as XRCC1, ERCC1, and XPD, involved in DNA repair, have been studied in only a few studies and have shown inconsistent results.
Conclusion: Results of pharmacogenetic studies will contribute to personalized treatment, nevertheless, they require confirmation in large prospective clinical trials of toxicity and survival. Other candidate genes acting in the complex process of metabolism of chemotherapeutic agents and pharmacokinetic aspects as well as lifestyle factors should be considered in future studies.