Relevance Research Of UGTlAl*28Polymorphism In Irinotecan-induced Adverse Reactions And Efficacy

[Background and Objective]Drug genetic polymorphism include drug metabolizing enzymes,receptors and targetingpolymorphism, which led to the individual differences in drug efficacy and adversereactions.Pharmacogenomics develops from drug genetic polymorphism,Pharmacogenomics study differences of gene sequence and its impact on the efficacyand adverse reactions to reveal these differences at the genetic level. Topoisomerase Ⅰinhibition-Inirotecan(CPT-11), was used in the therapy of advanced colorectal cancer atfirst,while has been widely used in other solid tumors,such as lung cancer,stomachcancer,cervical cancer,etc recently. Its characteristic side effects-delayed diarrhea limitits wider application. UGT1A1gene polymorphism was found associated withirinotecan chemotherapy-related toxicity.The purpose of this paper is to study UGT1A1distribution in patients with malignant tumors,and to explore its relationship withtoxicity and efficacy of irinotecan.[Methods]Forty-two blood samples of the patients with malignancy treated with irinotecan inoncology departmet of The Militiry General Hospital of Beijing PLA (December2011to December2012)were collected. Genomic DNA was extracted from peripheral bloodto examine the frequency of UGT1A1TATA box (TA) repeats, with amplifying genefragments using PCR and direct sequencing analysis of the polymorphism UGT1A1*28.The relationship of the UGT1A1*28polymorphism with the adverse reaction andefficacy of irinotecan was analyzed. [Results]1The distribution of UGT1A1genotypes:42patients blood specimen were collected，32cases （76.2%）were the wild genotype (TA)6/6,10cases (23.8%) were heterozygousTA6/7，homozygousTA7/7were rare(0).2The occurrence of adverse reactions:12of42cases (28.6%) were found delayeddiarrhea,10cases (24.8%) degreeⅠ-Ⅱand2cases(4.8%) degree Ⅲ-Ⅳ;Neutropeniaoccurs in36cases (85.7%),25cases (59.5%) degreeⅠ-Ⅱand11cases(26.2%) degreeⅢ-Ⅳ.3The relationship between UGT1A1genotypes and adverse reactions:The incidencerate of overall delayed diarrhea in patients with genotype TA6/6was lower than that inpatients with heterozygous TA6/7（18.8%vs60%，P=0.033）and so was degree Ⅲ-Ⅳneutropenia（15.6%vs60%，P=0.022）.There was no significant difference in theincidence rate of degree Ⅲ-Ⅳ delayed diarrhea(0%vs20%,) and overallneutropenia(84.4%vs90%)，P＞0.05。4The relationship between dose intensity and adverse reactions:The incidence rates ofneutropenia in patients with≥75mg/m2/w,50-74mg/m2/w,＜50mg/m2/w were95.8%,81.8%and57.1%. The rate in patients with≥75mg/m2/w is higher than that inpatients with50-74mg/m2/w and＜50mg/m2/w (P=0.028and P=0.033).But there wasno significant difference in the incidence rate of delayed diarrhea in patients with≥75mg/m2/w,50-74mg/m2/w,＜50mg/m2/w were41.7%,18.2%and0%(P=0.066andP=0.259). There was no significant difference,P＞0.05.5The relationship between UGT1A1genotypes and efficacy:26cases were assessablefor efficacy,include0CR,6PR10SD and10PD,the effective rate was23.1%（6/26）.There was no significant difference in objective response rates (25%vs16.7%)and disease control rates (65%vs50%) between the genotype TA6/6and heterozygousTA6/7, P＞0.05. [Conclusions]1In this study, UGT1A1gene promoter the wild genotype TA6/6was mostcommon,heterozygous TA6/7was more，homozygousTA7/7was last.2There was no significant correlation in the incidence of delayed diarrhea and doseintensity. UGT1A1gene promoter polymorphism was the significant influencing factorof delayed diarrhea, in the incidence of delayed diarrhea in patients with genotypeTA6/7was high.3There was positively correlation in the incidence of neutropenia and dose intensity,The patients with the higher dose intensity may be more prone to reduction inneutropenia,and in the incidence rate of severity(degree Ⅲ-Ⅳ) neutropenia in patientswith genotype heterozygous TA6/7was high.4There was no significant correlation in the efficacy of irinotecan between the genotypeTA6/6and heterozygous TA6/7.