Genetic polymorphisms related to fluoropyrimidine sensitivity and toxicity
Terashima, M.
Gan to Kagaku Ryoho. Cancer and ChemoTherapy 35(7): 1101-1104
2008
ISSN/ISBN: 0385-0684 PMID: 18633250 Document Number: 620541
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.