Genetic Polymorphisms of Drug-Metabolising Enzymes and Drug Transporters in the Chemotherapeutic Treatment of Cancer

Abstract

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.

Genetic Polymorphism of Metabolic Enzymes P450 (CYP) as a Susceptibility Factor for Drug Response, Toxicity, and Cancer Risk

“…Pseudogenes are also present in some CYPs involved in endogenous metabolism (CYP21P), but there is signifi cantly less variability than in CYP families 1 to 3. Inter-ethnic and inter-racial differences in frequencies of polymorphic gene variants are also worth noting (32).…”

Interactions of attention-deficit/hyperactivity disorder therapeutic agents with the efflux transporter P-glycoprotein

“…Interindividual differences in drug transporter activity mediated by genetic polymorphisms and drug interactions are important determinants of individual drug response and disposition of drug and metabolites (Beringer and Slaughter, 2005;Bosch et al, 2006). P-glycoprotein is the most well-studied member of the adenosine triphosphate-binding cassette (ABC) transporter superfamily, and has been found in a large number of normal tissues including intestine, liver, placenta, kidney, and the blood-brain barrier.…”

Genetic Bases for Predisposition to Common Multifactorial Disease in Man. Part II

“…Irinotecan is converted to its active metabolite SN-38 in humans, which is an inhibitor of topoisomerase I. Uridine diphosphoglucuronosyl transferase 1A1 (UGT1A1) is the enzyme responsible for detoxifi cation of the irinotecan active metabolite (7,48). Variations in UGT1A1 activity most commonly arise from polymorphisms in the UGT1A1 promoter region that contains several repeated TA elements.…”