Study On The Relationship Between UGT1A1 Gene Polymorphism And SN-38 Blood Concentration,Adverse Reactions And Efficacy Of Irinotecan

Irinotecan（CPT-11）is mainly used for metastatic colorectal cancer.Its metabolite,7-ethyl-10-hydroxycamptothecin（SN-38）,is an inhibitor of DNA topoisomerase I,which mainly acts on the S phase of cell cycle,inhibits the repair of DNA single strand breaks,interferes with DNA replication and transcription,and leads to tumor cell death.The effective rate of treatment is high,but the incidence of adverse reactions is also high,mainly diarrhea,vomiting,neutropenia,which limits its wide clinical application.Therefore,it is of great significance to study and explore the toxicity of irinotecan and the predictive factors of its efficacy for improving its safety and effectiveness.According to the inclusion and exclusion criteria,65 patients with colorectal cancer treated with irinotecan in The First Affiliated Hospital of Hebei North University were selected.The gene polymorphism of UGT1A1*6 and UGT1A1*28 was determined by Pyrosequencing,the plasma concentration of irinotecan active metabolite SN-38 was determined by high-performance liquid chromatography,and the adverse reactions in the course of chemotherapy were observed.The serious adverse reactions and curative effects,UGT1A1 gene polymorphism and SN-38 blood concentration were analyzed Degree.The results showed that there were 50 patients with UGT1A1*28wild type*1/*1,15 patients with heterozygous mutation*1/*28,43patients with UGT1A1*6 wild type*1/*1,20 patients with heterozygous mutation*1/*6,and 2 patients with homozygous mutation*6/*6.The incidence of grade 3-4 delayed diarrhea in patients with UGT1A1*28 and UGT1A1*6 mutation was significantly higher than that in patients with wild type（P<0.05）,but there was no significant difference in grade 3-4neutropenia（P>0.05）;There was no difference in ORR and DCR in patients with UGT1A1*28（P>0.05）,The DCR of patients with UGT1A1*6 mutation was significantly lower than that in patients with wild type（P<0.01）.The mean peak blood concentration of SN-38 was 42.83ng·m L^-1 and the mean valley value was 14.27ng·m L^-1 in 50 patients with UGT1A1*28 wild type.There was no significant difference in the risk of grade 3-4 delayed diarrhea and neutropenia in patients with peak and valley blood concentrations greater than the mean（P>0.05）.the ORR and DCR were significantly higher（P<0.05）.The mean peak and valley concentrations of SN-38 in 15 patients with UGT1A1*28 heterozygous mutation were 49.56 ng·m L^-1 and 16.25 ng·m L^-1,respectively.The incidence of grade 3-4 delayed diarrhea and neutropenia was significantly higher in patients with higher than average blood concentrations of SN-38than in patients with lower than average blood concentrations（P<0.05）,but there was no significant difference in total ORR and DCR（P>0.05）.The mean peak and valley blood concentrations of SN-38 in 43 patients with UGT1A1*6 wild type were 43.56 ng·m L^-1 and 13.57 ng·m L^-1,respectively.The risk of grade 3-4 delayed diarrhea and neutropenia was not significantly different in patients whose blood concentration of SN-38was greater than the mean（P>0.05）,but the ORR and DCR were significantly higher than those whose blood concentration was lower than the mean（P<0.05）.The mean peak and valley blood concentrations of SN-38 in 22 patients with UGT1A1*6 mutation were 45.99 ng·m L^-1and16.98 ng·m L^-1,respectively.The incidence of grade 3-4 delayed diarrhea was significantly higher in patients with blood drug concentration above the mean（P<0.05）,but there was no significant difference in the incidence of neutropenia,ORR,and the DCR（P>0.05）.For UGT1A1*6 wild type patients and UGT1A1*28 wild type patients,the ORR and DCR of the patients whose SN-38 peak and valley blood concentration are higher than the mean value are significantly higher than those whose blood concentration is lower than the mean value,but there is no significant difference in the risk of grade 3-4 delayed diarrhea and neutropenia.For the patients with UGT1A1*6 mutation and the patients with UGT1A1*28 heterozygous mutation,the risk of grade 3-4 delayed diarrhea in the patients with SN-38 peak and glutamic concentration higher than the mean was significantly higher than that in the patients with peak and glutamic concentration lower than the mean,but there was no significant difference in ORR and DCR.