Pharmacogenetics and folate metabolism -- a promising direction

Folate metabolism is the target of two major drug groups: folate antagonists (e.g., methotrexate) and thymidylate synthase inhibitors (for example, 5-fluorouracil). These agents are widely used in cancer chemotherapy, as treatment for rheumatoid arthritis, and for other conditions. The administration of these drugs in cancer chemotherapy can induce a state of acute folate depletion with sometimes life-threatening toxic sequelae. Recent studies suggest that polymorphisms in folate-metabolizing enzymes may modify the therapeutic effectiveness and toxicity of drugs targeting folate metabolism. This review briefly summarizes major drugs targeting the folate pathway and describes common polymorphisms in folate-metabolizing enzymes and transport proteins. Pharmacogenetic studies investigating the relevance of these polymorphisms with respect to patients' response to antifolate chemotherapeutic agents are discussed. Investigating genetic variability in folate metabolism in the framework of pharmacogenetics is a promising field. Findings to date illustrate the potential for targeting therapy based on patients' genotypes with improved outcomes and reduced toxicity.