TPMT, UGT1A1 and DPYD: genotyping to ensure safer cancer therapy?
The Food and Drug Administration (FDA) has approved label changes for two anticancer drugs, 6-mercaptopurine (6-MP) and irinotecan, to include pharmacogenetic testing as a potential means to reduce the rate of severe toxic events. Comprehensive evaluation of the clinical benefit and cost effectiveness of screening strategies with these tests has not been completed. However, the FDA decided that evidence indicates sufficient benefit to warrant informing prescribers, pharmacists and patients of the availability of pharmacogenetic tests and their possible role in the selection and dosing of these anticancer agents. Reviewing the gene-drug-phenotype relationships of 6-MP, irinotecan and 5-fluorouracil reveals properties of these relationships that lead to a clinically useful pharmacogenetic test. Research in the near future should clarify the role of pharmacogenetic testing in reducing the risk of severe toxicity and determine how these same tests might identify a subset of patients who should safely receive higher doses of treatment to derive the same benefit as the rest of the patient population.
Maitland
Michael L
ML
Department of Medicine, Committee on Clinical Pharmacology and Pharmacogenomics, and Cancer Research Center, University of Chicago, Chicago, IL 60637, USA.
Vasisht
Kaveeta
K
Ratain
Mark J
MJ
D002166:Camptothecin / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D015122:Mercaptopurine / Q000378:metabolism / Q000627:therapeutic use; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D010597:Pharmacogenetics / Q000379:methods / Q000639:trends; D016896:Treatment Outcome; D000099148:UGT1A1 Enzyme
D002166:Camptothecin; D042943:Dihydrouracil Dehydrogenase (NADP); D014453:Glucuronosyltransferase; D000077146:Irinotecan; D015122:Mercaptopurine; D008780:Methyltransferases; D000099148:UGT1A1 Enzyme; C022745:thiopurine methyltransferase