Genetic polymorphisms of drug-metabolising enzymes and drug transporters in the chemotherapeutic treatment of cancer.
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 reactions. Polymorphisms in genes coding for metabolising enzymes and drug transporters can affect drug efficacy and toxicity. Pharmacogenetics aims to identify individuals predisposed to a high risk of toxicity and low response from standard doses of anti-cancer drugs. This review focuses on the clinical significance of polymorphisms in drug-metabolising enzymes (cytochrome P450 [CYP] 2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, dihydropyrimidine dehydrogenase, uridine diphosphate glucuronosyltransferase [UGT] 1A1, glutathione S-transferase, sulfotransferase [SULT] 1A1, N-acetyltransferase [NAT], thiopurine methyltransferase [TPMT]) and drug transporters (P-glycoprotein [multidrug resistance 1], multidrug resistance protein 2 [MRP2], breast cancer resistance protein [BCRP]) in influencing efficacy and toxicity of chemotherapy. The most important example to demonstrate the influence of pharmacogenetics on anti-cancer therapy is TPMT. A decreased activity of TPMT, caused by genetic polymorphisms in the TPMT gene, causes severe toxicity with mercaptopurine. Dosage reduction is necessary for patients with heterozygous or homozygous mutation in this gene. Other polymorphisms showing the influence of pharmacogenetics in the chemotherapeutic treatment of cancer are discussed, such as UGT1A1*28. This polymorphism is associated with an increase in toxicity with irinotecan. Also, polymorphisms in the DPYD gene show a relation with fluorouracil-related toxicity; however, in most cases no clear association has been found for polymorphisms in drug-metabolising enzymes and drug transporters, and pharmacokinetics or pharmacodynamics of anti-cancer drugs. The studies discussed evaluate different regimens and tumour types and show that polymorphisms can have different, sometimes even contradictory, pharmacokinetic and pharmacodynamic effects in different tumours in response to different drugs. The clinical application of pharmacogenetics in cancer treatment will therefore require more detailed information of the different polymorphisms in drug-metabolising enzymes and drug transporters. Larger studies, in different ethnic populations, and extended with haplotype and linkage disequilibrium analysis, will be necessary for each anti-cancer drug separately.
Bosch
Tessa M
TM
Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands. aptbo@slz.nl
Meijerman
Irma
I
Beijnen
Jos H
JH
Schellens
Jan H M
JH
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D042943:Dihydrouracil Dehydrogenase (NADP); D008780:Methyltransferases; C022745:thiopurine methyltransferase; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D015238:Sulfotransferases