The Prediction Of UGT1A1, TS Gene Polymorphism On The Patients Received FOLFIRI Regimen

Aim:Irinotecan (CPT-11) in combination fluorouracil (5-FU) is one of the two major regimens for advanced colorectal caner treatment. Diarrhea and neutropenia are two well-characterized adverse events associated with CPT-11treatment. Due to concern for these events, the utilization of CPT-11-based regimen has been largely restricted in clinic in our country.Advances in the field of pharmacogenomics have provided a link between genetic polymorphisms and response to CPT-11treatment. UGT1A1and TS are important enzymes involved in efficacy, toxicity, and pharmacokinetics of irinotecan and5-Fu, respectively. Compre-hensive analysis of the frequency of polymorphisms and the influence of genetic variation in these two genes will be helpful to determine the inter-enthic difference in clinical outcome of CPT-11-based treatment, and to identify the patients who may need dose adjustment of CPT-11.Method:From March2011to November2011, a total of41advanced colorectal cancer patients assigned to receive CPT-11combined with5FU regimen. Genomic DNAs were isolated from peripheral blood samples using chloroform method. PCR amplifications and Restriction fragment length polymorphism were performed for genetic polymer-phism analysis of UGT1A1and TS. We assessed the efficacy, toxicity and survival in patient treated with CPT-11in combination with5-FU, and analyzed the relationship between genetic polymorphism of UGT1A1and TS and clinical outcome.Results:1、Forty-one patients had analysis in UGT1A1and TS, respectively. The frequencies of UGT1A1genotypes in patients were significant different from Caucasian patients. The frequency of the wild-type UGT1A1*28(TA6/6) and TS(3gG/3G) were higher compared with those in Caucasian patients. It was reported the polymorphism of UGT1A1*6was not detected in Caucasian population2、Analysis of efficacy results show tha: the differences between UGT1A1*6points and the UGT1A1*28sites inwild-type and mutant type of efficiency were not statistically significant. Logistic regression analysis showed that age, gender, ECOG performance score, the UGT1A1gene polymorphism, the TS gene polymorphism had no effect on the efficacy.3、As compared with TA6/6,、TA6/7and TA7/7genotypes, patients who carry wild-type UGT1A1*28had a significant decrease of grade2to4diarrhea and grade3to4neutropenia. However, there is a trend for higher incidence of grade2to4diarrhea and grade3to4neutropenia in G/G genotype compared with those in A/A genotype in this study. According to the influence on activity of mRNA transcription, TS genotype was divided into three arms:homozygous3G arm, hetero-zygous3G(3G/3C,3G/2R) arm, and no3G(3C/3C,2R/2R,3C/2R) inclu- ded arm.There were no significant differences in grade3to4diarrhea or neutropenia among the three arms.4、The combination to predict the toxicity of the UGT1A1gene and TS gene, compared with pure UGT1A1*28specificity of the prediction accuracy slightly increased, but more sensitive than single factor forecast to decline.Conclusion:Our study suggests that the incidence of toxicity of CPT-11combined with5-FU in the patients in our hospital was lower, and the major reason was the difference in genetic polymorphism between Chinese and Caucasian patients. The UGT1A1polymorphism could affect the efficacy, toxicity and pharmacokinetics of CPT-11combined with5-FU regimen, but the value of TS polymorphism was limited and need to be further investigated.