Volume 5, Number 10, Supplement 12 (October 2008)

Cancer Genetics

1

The role of pharmacogenetics in the management of fluorouracil-based toxicity

L. Wayne Keiser, MD

Redwood Regional Medical Group, Santa Rosa, CA

Fluorouracil (5-FU) and its oral pyrimidine analog capecitabine are widely used for treatment of a variety of solid human tumors, particularly colorectal cancer. The toxicity associated with these agents, however, is often significant and may limit therapy. Major adverse effects of 5-FU–based chemotherapy include diarrhea, stomatitis, nausea/vomiting, and hand-foot syndrome. Severe (grade 3/4) toxicity related to 5-FU–based chemotherapy occurs in up to one third of patients. Approximately half of all serious adverse events resulting from 5-FU–based therapy are due to deficiencies in key enzymes involved in 5-FU metabolism. Mutations or genetic polymorphisms in the genes that encode the enzymes dihydropyrimidine dehydrogenase and thymidylate synthetase can decrease enzyme activity and result in excess amounts of 5-FU that can produce severe toxicity. New pharmacogenetic testing methods can identify such variants and thus indicate those patients who are at greatest risk for adverse effects with 5-FU or capecitabine therapy. These individuals may require closer monitoring, dose reductions, or alternative therapy to minimize treatment-related toxicity and thus maintain treatment. Such genotype-based methods are helping to develop customized approaches to cancer therapy that can reduce toxicity and improve patient outcomes.

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Funding for this publication was provided by Myriad Genetic Laboratories, Inc.

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