[Genetic polymorphisms related to fluoropyrimidine sensitivity and toxicity].
Fluoropyrimidine such as 5-fluorouracil(5-FU)exerts its antitumor activities via anabolism by several enzymes. Genetic polymorphisms of these enzymes related to sensitivity and toxicity of fluoropyrimidines are reviewed. Expression of thymidylate synthase(TS), a target enzyme of 5-FU, is regulated by variable number of a 28 bp tandem repeat in the enhancer region. The double tandem repeat is associated with low TS expression, and consequently, patients with double tandem repeat demonstrated higher sensitivity to 5-FU than those with triple tandem repeat. Single nucleotide polymorphism within the second tandem repeat and loss of heterozygosity are also reported to be related to fluoropyrimidine sensitivity. In addition, patients having a 6 bp deletion in 3'-UTR region showed remarkably high antitumor activity by 5-FU based chemotherapy. Genetic variations in 5-FU catabolic enzymes can also have a profound effect on 5-FU toxicity. So far 39 mutations/ polymorphisms have been identified in dihydropyrimidine dehydrogenase(DPD)gene, a major catabolic enzyme of 5- FU. Among them, IVS14+1G>A is reported to be highly associated with severe toxicity caused by chemotherapy with fluoropyrimidine. A polymorphism that may influence the efficacy of 5-FU by influencing folate pools is that of the methylenetetrahydrofolate reductase(MTHFR)gene. C677T mutation was associated with a higher response rate on 5-FU/folinic acid chemotherapy. Prospective clinical trials to confirm the predictability of genetic polymorphism for sensitivity and toxicity of 5-FU should be performed.
Terashima
Masanori
M
Division of Gastric Surgery, Shizuoka Cancer Center, Sunto-gun, Shizuoka, Japan.
D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics / Q000378:metabolism; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics*; D011743:Pyrimidines / Q000009:adverse effects* / Q000378:metabolism / Q000627:therapeutic use*; D012680:Sensitivity and Specificity; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism
D011743:Pyrimidines; C029269:5-fluoropyrimidine; D042943:Dihydrouracil Dehydrogenase (NADP); D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase