Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.67 (thiopurine methyltransferase)
 551 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pharmacogenetics has emerged as a novel and challenging area of interest in oncology. Cancer chemotherapy is characterized by major intersubject variability in tumor responses and host toxicity. This variation may be caused by genetic differences in the enzymes involved in the metabolism of anticancer agents. Anticancer agents, such as 6-mercaptopurine, 5-fluorouracil, and irinotecan, have a narrow therapeutic index that can sometimes result in severe life-threatening toxicities. The impact of polymorphisms in metabolizing enzymes (thiopurine S-methyltransferase, dihydropyrimidine dehydrogenase, and uridine diphosphate glucuronosyltransferase) that participate significantly in the disposition of these anticancer agents is discussed.
 ...
PMID:Inherited variations in drug-metabolizing enzymes: significance in clinical oncology. 1067 43

Dose adjustment of drug administration for each patient has been performed based on counts of some factors such as body surface area, age of the patient, performance status, renal and/or liver function. Pharmacokinetic and pharmacodynamic analyses have been investigated by measuring the plasma concentration of a drug and observing the drug effects. However, prior to drug administration it is difficult to predict unexpected, severe drug toxicity, which depends on the individual differences among patients. Recent progress in human genome analysis has been providing tools for new approaches to disease treatment based on individual differences using genetic information. This review focuses on the drug metabolizing enzyme and its genetic polymorphisms in cancer chemotherapy. We describe the recent findings on pharmacogenomics between toxicity and the genetic polymorphisms of the thiopurine methyltransferase (TPMT) gene, dihydropyrimidine dehydrogenase (DPYD) gene, methylenetetrahydrofolate reductase (MTHFR) gene, and uridine diphosphate glucuronosyltransferase (UGT1A1 and UGT1A7) gene. We need to accumulate clinical data based on the variation of genetic profiling as well as pharmacogenetic information. Such data will help tailor cancer chemotherapy to an individual's predisposition in the near future.
 ...
PMID:[Pharmacogenomic approaches for prevention of drug toxicity in cancer chemotherapy]. 1266 88

Drug-metabolizing enzymes are responsible for the activation or detoxification of cytotoxic drugs. Allelic variants are present with a variable frequency in different populations around the world and have an important role in the therapeutic index of such drugs. It is known that polymorphisms in thiopurine methyltransferase and dihydropyrimidine dehydrogenase have been associated with altered drug metabolism and increased risk of severe toxicity from 6-mercaptopurine and 5-fluorouracil, respectively. Additionally, a variant number of dinucleotide-repeat sequences in the promotor for uridine 5'-diphosphate glucuronosyltransferase 1A1 influences the glucuronidation of SN-38, the active metabolite of irinotecan, which is associated with severe toxicity, including diarrhea and neutropenia. In the same way, polymorphisms in thymidylate synthase have been associated with pyrimidine-associated toxicity and also with response to chemotherapy. The examples shown in this review demonstrate the usefulness of pre-screening patients for well-characterized polymorphism to identify the best-tolerated and most-effective treatment.
 ...
PMID:Genetic determinants of cancer drug efficacy and toxicity: practical considerations and perspectives. 1616 69

Drug metabolism enzymes (DME) play a significant role in drug detoxification and activation, which exert important effect on drug efficacy and sensitivity to toxicity. There is difference in expression and activity of DME between in tumor tissue and in non-tumor tissue. DME related with tumor chemotherapy are cytochrome P450 (CYP), glutathione-S-transferase (GST), uridine diphospho-glucuronosyltransferase (UGT), thiopurine methyltransferase (TPMT) and dihydropyrimidine dehydrogenase (DPD). The enzymes above are inducible and genetic polymorphic, thus with variable activity in individuals.
 ...
PMID:[Cancer chemotherapy and drug metabolism enzyme]. 1640 65

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.
 ...
PMID:Genetic polymorphisms of drug-metabolising enzymes and drug transporters in the chemotherapeutic treatment of cancer. 1650 59

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.
 ...
PMID:Pharmacogenomics of drug-metabolizing enzymes and drug transporters in chemotherapy. 1837 Feb 31