Pharmacogenomics of drug-metabolizing enzymes and drug transporters in chemotherapy.
There is wide variability in the response of individuals to standard doses of drug therapy. This is an important problem in clinical practice, where it can lead to therapeutic failures or adverse drug events. Polymorphisms in genes coding for metabolizing enzymes and drug transporters can affect drug efficacy and toxicity. Pharmacogenomics aims to identify individuals predisposed to high risk of toxicity and low response from standard doses of anticancer drugs. This chapter focuses on the clinical significance of polymorphisms in drug-metabolizing enzymes and drug transporters in influencing efficacy and toxicity of anticancer therapy. The most important examples to demonstrate the influence of pharmacogenomics on anticancer therapy are thiopurine methyltransferase (TPMT), UGT (uridine diphosphate glucuronosyltransferase) 1A1*28, and DPD (dihydropyrimidine dehydrogenase) *2A, respectively, for 6-mercaptopurine, irinotecan, and 5-fluorouracil therapy. However, in most other anticancer therapies no clear association has been found for polymorphisms in drug-metabolizing enzymes and drug transporters and pharmacokinetics or pharmacodynamics of anticancer drugs. Evaluation of different regimens and tumor types showed that polymorphisms can have different, sometimes even contradictory, pharmacokinetic and pharmacodynamic effects in different tumors in response to different drugs. The clinical application of pharmacogenomics in cancer treatment therefore requires more detailed information regarding the different polymorphisms in drug-metabolizing enzymes and drug transporters. A greater understanding of complexities in pharmacogenomics is needed before individualized therapy can be applied on a routine basis.
Bosch
Tessa M
TM
Clinical Pharmacy & Toxicology, Medical Center Rijnmond-Zuid, Rotterdam, The Netherlands.
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001711:Biotransformation / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D018579:Patient Selection; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D016896:Treatment Outcome
C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D026901:Membrane Transport Proteins; D009363:Neoplasm Proteins; D003577:Cytochrome P-450 Enzyme System; D042943:Dihydrouracil Dehydrogenase (NADP); D008780:Methyltransferases; C022745:thiopurine methyltransferase; D014453:Glucuronosyltransferase