S-1 is an oral
antitumor agent that contains
tegafur, which is converted to
fluorouracil (5-FU) in the human body.
Cytochrome P450 2A6 (CYP2A6) is the principal
enzyme responsible for bioconversion of
tegafur to
5-FU. A number of CYP2A6 polymorphisms have been associated with variations in
enzyme activity in several ethnic populations. The CYP2A6*4C allele leads to deletion of the entire CYP2A6 gene, and is the main finding in patients with reduced CYP2A6 enzymatic activity. Thus, the aim of our study was to evaluate the allele frequencies of CYP2A6 polymorphisms in a population with
cancer of the digestive system. We developed a simple screening method, which combined TA cloning and direct-sequencing, to detect CYP2A6 genetic polymorphisms in Chinese patients with
cancers of the digestive system. A total of 77 patients with various types of
digestive system cancers were 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 and 12%, respectively. As expected, patients that were determined to be homozygous for CYP2A6*4C exhibited the characteristic
chemotherapy efficacy and toxicity profiles. The TA cloning-based direct sequencing method facilitated allele frequency and genotyping determination for CYP2A6*1A, 1B and 4C of
cancer patients. The findings indicated that the population carries a high frequency of the CYP2A6*4C homozygous genotype. Thus, the reduced efficacy of standard
chemotherapy dosage in Chinese
cancer patients may be explained by the lack of CYP2A6-mediated S-1 bioconversion to
5-FU.