Pharmacogenetics: a tool for individualizing antineoplastic therapy.
This article reviews the clinical relevance of pharmacogenetics in cancer chemotherapy, with emphasis on drugs for which genetic differences in enzyme metabolism have been demonstrated to affect patient outcome. About 10% of children with leukaemia are intolerant to mercaptopurine (6-mercaptopurine) because of genetic defects in mercaptopurine inactivation by thiopurine S-methyltransferase. However, mercaptopurine dose intensity, a critical factor for outcome in patients deficient in thiopurine S-methyltransferase, can be maintained by means of thiopurine S-methyltransferase phenotyping or genotyping. Patients with reduced fluorouracil (5-fluorouracil) catabolism are more likely to be exposed to severe toxicity. The measurement of dihydropyrimidine dehydrogenase activity in patients cannot be considered fully predictive, and the role of dihydropyrimidine dehydrogenase gene variants in this syndrome has yet to be clarified. With regard to irinotecan, patients with Gilbert's syndrome phenotype have reduced inactivation of the active topoisomerase I inhibitor 7-ethyl-10-hydroxycamptothecin (SN-38) caused by a mutation in the UDP-glucuronosyltransferase 1A1 gene promoter. This subset of patients is more likely to be exposed to irinotecan toxicity and could be identified by genotyping for gene promoter variants. Finally, the experience with amonafide represents a model for dose individualization approaches that use simple phenotypic probes.
Innocenti
F
F
Department of Medicine, The University of Chicago, Illinois 60637, USA.
Iyer
L
L
Ratain
M J
MJ
D000225:Adenine; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000378:metabolism*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000378:metabolism; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil / Q000009:adverse effects / Q000378:metabolism; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D007094:Imides / Q000378:metabolism; D000077146:Irinotecan; D007546:Isoquinolines / Q000378:metabolism; D015122:Mercaptopurine / Q000009:adverse effects / Q000378:metabolism; D008780:Methyltransferases / Q000235:genetics; D053644:Naphthalimides; D063065:Organophosphonates; D010088:Oxidoreductases / Q000172:deficiency / Q000235:genetics; D010597:Pharmacogenetics; D010641:Phenotype; D000099148:UGT1A1 Enzyme
D000225:Adenine; D000970:Antineoplastic Agents; D002166:Camptothecin; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil; D014453:Glucuronosyltransferase; D007094:Imides; D000077146:Irinotecan; D007546:Isoquinolines; D015122:Mercaptopurine; D008780:Methyltransferases; D053644:Naphthalimides; D063065:Organophosphonates; D010088:Oxidoreductases; D000099148:UGT1A1 Enzyme; C037020:amonafide; C022745:thiopurine methyltransferase