Pharmacogenetics of folate-related drug targets in cancer treatment.
Folate metabolism is the target of two major drug groups: folate antagonists (for example, methotrexate) and thymidylate synthase inhibitors (for example, 5-fluorouracil). These agents are used in the treatment of cancer, as well as for other conditions, such as rheumatoid arthritis. High-dose cancer treatment protocols can induce a state of acute folate depletion which may lead to significant treatment-related toxicity. Polymorphisms in folate-metabolizing enzymes may modify the therapeutic effectiveness and toxicity of these drugs. This review briefly summarizes the drugs targeting the folate pathway and describes common polymorphisms in folate-metabolizing enzymes and transport proteins. Pharmacogenetic studies investigating folate-related drug targets in the treatment of colorectal cancers and hematologic malignancies will subsequently be discussed. Findings to date illustrate a potential for targeting therapy based on patients' genotypes, in order to improve outcomes and reduce toxicity. However, larger, well-designed studies are needed to confirm these early findings.
Robien
Kim
K
Fred Hutchinson Cancer Research Center, Cancer Prevention Program, 1100 Fairview Ave N, M4-B402, Seattle, WA 98109 1024, USA.
Boynton
Alanna
A
Ulrich
Cornelia M
CM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use; D005492:Folic Acid / Q000235:genetics* / Q000378:metabolism*; D005493:Folic Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology / Q000627:therapeutic use; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000627:therapeutic use
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D005492:Folic Acid; D013940:Thymidylate Synthase; D005472:Fluorouracil; D008727:Methotrexate