| Background and objective:Cancer has become a kind of chronic disease which has a high incidence and mortality rate, especially the gastrointestinal tumor. Approximately50%of patients who underwent radical operation developed recurrence or metastasis. Irinotecan could significantly improve the survival and curative effect of advanced gastric cancer when used as a treatment after the failure of first-line or second-line chemotherapy by5-FU. However, severe toxicity has restrict its clinical application and significant individual difference of the toxicity was also exist. Thus, searching the predictable factors for irinotecan toxicity in order to provide a guide for clinic becoming more and more important.Polymorphisms of the drug metabolic enzyme is one dominant factor that cause the individual differences. Uridine diphosphate-glucuronate transferase1A1(UGT1A1) is the main metabolic enzyme of SN-38which is the active metabolite of irinotecan, it dicides the biotransformation between active metabolite SN-38and inactive metabolite SN-38G and polymorphisms in UGT1A1gene can directly affect the individual difference of curative effect and toxicity. In addition, P-glycoprotein, encoded by ABCB1gene, is one of the most important membrane transport protein in liver, which works as an efflux pump to transport natural products and toxins. Irinotecan and its metabolites are both subtrates of P-glycoprotein and researches have suggest that polymorphisms in ABCB1gene is also a factor that cause individual difference of metabolism and toxicity of irinotecan. This study would explore the relationship between UGT1A1*6/*28and ABCB13435C>T and irinotecan toxicity, and provide an evidence for the safety of irinotecan.Meterials and Methods:1. Subjects and tissue preparationA total of85unrelated patients were enrolled in this study, patients were all from the oncology department of the First Affiliated Hospital of ZhengZhou University. Patients are Han in Henan province,54were male(63.5%) and31were female(36.5%), age ranges from22to78years old. All patients were confirmed by pathology or CT and no severe infectious disease and other complication such as cardiopathy, bleed, diabetes mellitus were found. Among them,11patients were gastric cancer(12.9%),35patients were colorectal cancer(41.2%),11patients were small cell lung cancer(12.9%),13patients were esophagus cancer(15.3%),16patients were differentiated adenocarcinoma and other tumor(18.8%). Three chemotherapy methods were applicated:FOLEFIRI, IROX, cetuximab and irinotecan.2. MethodsGenotyping assay were performed according to UGT1A1*6, UGT1A1*28and ABCB13435C>T. First, DNA were extracted by Phenol-Chloroform, and secondly, Polymerase Chain Reaction(PCR) were performed to get the target DNA segment, then the PCR products were sequenced to analyse polymorphisms of UGT1A1*6, UGT1A1*28and ABCB13435C>T.Severe adverse effects were monitored and classified by the standard of NCI-C:TC(version3.0). Data was analysed by SPSS13.0, the difference of severe adverse effects between different genotypes were analysed by chi-square test or Fisher’s exact test. Results:1.Influence of UGT1A1*6polymorphism on the adverse effect of irrinotecanAmong the enrolled85patients,46(54.1%),30patients(35.3%),9patients were identified with UGT1A1*6wild type genotype(GG), UGT1A1*6heterozygote (GA) and UGT1A1*6homozygote(AA),respectively. Among GG genotype,l patient(2.17%) has occurred grade3or4diarrhea,4patients(8.70%) have occurred grade3or4neutropenia,2patients(4.35%) have occurred grade3or4leukopenia,4patients(8.70%) have occurred grade3or4hemoglobin decrease. To UGT1A1*6heterozygote (GA),2patients(6.67%) have occurred grade3or4diarrhea,5patients(16.67%) have occurred grade3or4neutropenia,4patients(13.33%) have occurred grade3or4leukopenia,3patients(10.0%) have occurred grade3or4hemoglobin decrease. To UGT1A1*6homozygote(AA),3patients(33.3%) have occurred grade3or4diarrhea,3patients(33.3%) have occurred grade3or4neutropenia,2patients(22.22%) have occurred grade3or4leukopenia,2patients(22.22%) have occurred grade3or4hemoglobin decrease. UGT1A1*6homozygote (AA) could increase the risk of grade3or4diarrhea when compared with wild type(33.3%vs2.2%,p<0.05), it also has a trend to increase the risk of grade3or4leukopenia(33.3%vs8.7%, p=0.06).2.Influence of UGT1A1*28polymorphism on the adverse effect of irrinotecan64(75.3%) patients were identified with UGT1A1*28wild type genotype(TA6/6),2patients(9.4%) have occurred grade3or4diarrhea,3patients(14.1%) have occurred grade3or4neutropenia,2patients(9.4%) have occurred grade3or4leukopenia,2patients(9.4%) have occurred grade3or4hemoglobin decrease.19patients(22.4%) were identified with UGT1A1*28heterozygote(TA6/7),3patients(14.3%) have occurred grade3or4diarrhea,3patients(14.2%) have occurred grade3or4neutropenia,2patients(9.5%) have occurred grade3or4leukopenia,2patients(9.5%) have occurred grade3or4hemoglobin decrease.2patients(2.3%) were identified with UGT1A1*28homozygote(TA7/7),1patients(4.8%) have occurred grade3or4leukopenia and no other adverse effects were observed. Both UGT1A1*28heterozygote and homozygote could increase the risk of grade3or4diarrhea(15.8%vs3.1%,p<0.05), but not leucopenia(14.3%vs9.4%, p=0.06).3.Influence of ABCB1C3435T polymorphism on the adverse effect of irrinotecan34patients(40.0%) were identified with ABCB13435C>T wild type genotype(3435CC),2patients(5.8%) have occurred grade3or4diarrhea,2patients(5.8%) have occurred grade3or4neutropenia,2patients(5.8%) have occurred grade3or4leukopenia,2patients(5.8%) have occurred grade3or4hemoglobin decrease.36patients(42.4%) were identified with ABCB13435C>T heterozygote(3435CT),2patients(3.9%) have occurred grade3or4diarrhea,7patients(13.7%) have occurred grade3or4neutropenia,4patients(7.9%) have occurred grade3or4leukopenia,4patients(7.9%) have occurred grade3or4hemoglobin decrease.15patients(17.6%) were identified with ABCB13435C>T homozygote(3435TT),2patients(3.9%) have occurred grade3or4neutropenia,2patients(3.9%) have occurred grade3or4leukopenia,2patients(3.9%) have occurred grade3or4hemoglobin decrease. There is no significant difference between ABCB13435C>T genotypes, but a tendency was observed(grade3or4neutropenia,17.6%vs5.9%,p=0.08; leucopenia,11.8%vs5.9%,p=0.219).Conclusion:UGT1A1*28has a low frequency in Henan Han population while UGT1A1*6and ABCB13435C>T have high frequencies. UGT1A1*6homozygote and UGT1A1*28heterozygote/homozygote could increase the risk of grade3or4diarrhea significantly after irinotecan chemotherapy. Meanwhile, UGT1A1*6, UGT1A1*28and ABCB13435C>T polymorphisms have a trend to increase the risk of severe toxicity. |
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