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S-1 is an oral antitumor agent that contains tegafur, which is convertedto fluorouracil (5-FU) in the human body. Cytochrome P450 2A6 (CYP2A6) is theprincipal enzyme responsible for bioconversion of tegafur to 5-FU. A number ofCYP2A6 polymorphisms have been associated with variations in enzyme activity inseveral ethnic populations. The CYP2A6*4C allele leads to deletion of the entireCYP2A6 gene, and is the main finding in patients with reduced CYP2A6 enzymaticactivity. Thus, the aim of our study was to evaluate the allele frequencies ofCYP2A6 polymorphisms in a population with cancer of the digestive system. We developeda simple screening method, which combined TA cloning and direct-sequencing, todetect CYP2A6 genetic polymorphisms in Chinese patients with cancers of the digestivesystem. A total of 77 patients with various types of digestive system cancerswere screened for CYP2A6 genetic polymorphisms. The allele frequencies of CYP2A6*1A,CYP2A6*1B and CYP2A6*4C in the 77 patients screened were 62, 42 and 13%, respectively.Frequencies of the homozygous genotypes for CYP2A6*1A and CYP2A6*4C were 27 and12%, respectively. As expected, patients that were determined to be homozygousfor CYP2A6*4C exhibited the characteristic chemotherapy efficacy and toxicityprofiles. The TA cloning-based direct sequencing method facilitated allele frequencyand genotyping determination for CYP2A6*1A, 1B and 4C of cancer patients. Thefindings indicated that the population carries a high frequency of the CYP2A6*4Chomozygous genotype. Thus, the reduced efficacy of standard chemotherapy dosagein Chinese cancer patients may be explained by the lack of CYP2A6-mediated S-1bioconversion to 5-FU.

oncology reports

Characteristic CYP2A6 genetic polymorphisms detected by TA cloning-based sequencing in Chinese digestive system cancer patients with S-1 based chemotherapy