Pharmacogenetics of folate-related drug targets in cancer treatment

Pharmacogenomics. 2005 Oct;6(7):673-89. doi: 10.2217/14622416.6.7.673.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Fluorouracil / pharmacology
  • Fluorouracil / therapeutic use
  • Folic Acid / genetics*
  • Folic Acid / metabolism*
  • Folic Acid Antagonists / pharmacology
  • Folic Acid Antagonists / therapeutic use
  • Humans
  • Methotrexate / pharmacology
  • Methotrexate / therapeutic use
  • Models, Biological
  • Neoplasms / drug therapy*
  • Pharmacogenetics*
  • Polymorphism, Genetic*
  • Thymidylate Synthase / antagonists & inhibitors
  • Thymidylate Synthase / therapeutic use


  • Antineoplastic Agents
  • Folic Acid Antagonists
  • Folic Acid
  • Thymidylate Synthase
  • Fluorouracil
  • Methotrexate