A Study On The Relationship Between UGT1A1*28, UGT1A1*6 Polymorphism And The Toxicity Of Irinotecan-based Chemotherapy

Background and objective:The gastrointestinal cancer is a common malignant tumor in the world.It's incidence and mortality are high.Gastrointestinal cancer has the characteristics of easy to relapse and transfer.What's more,the early diagnosis rate of gastrointestinal cancer is still low in our country today.Many patients have been found distant metastases when the primary tumor is been diagnosed.Therefore,most of the patients with gastrointestinal cancer belong to advanced stage malignant tumor or metastasis cases.The five years survival rate of these patients is low,so they are need chemotherapy after surgery.Hence,the treatment for patients with gastrointestinal cancer is radical operation followed by chemotherapy now.Since the early 1990 s,the chemotherapy regimen contains 5-FU and CF had gradually became the first-line regimen.However,the efficacy of them is not so good.Therefore,people have overcame so many difficult to explore and finally invented many new anti-cancer drugs such as cytotoxic drugs in recent years.Irinotecan(CPT-11)is one of the representative of them.It is a semi synthetic soluble derivative of camptothecin.The emergence of the drug make a great progress of the treatment of patients with gastrointestinal cancer.The median survival time of the patients is prolonged,and so is the five years survival rate.CPT-11 is converted into its active metabolite(SN-38)by carboxylesterase.And then form a compound with topoisomerase I(TOPO I)and DNA.Finally,the compound interfere with DNA replication to exert anti-tumor cell activity by inhibiting TOPO I.Then SN-38 is turned into SN-38 G by UGT1A1 in liver.This shows that TOPO I is the target enzyme of CPT-11.while the UGT1A1 is the key enzyme in the metabolism of CPT-11.So in theory,the single nucleotide polymorphism(SNP)of UGT1A1 gene will affect the activity and expression of UGT1A1.And then affects the metabolism of irinotecan,in the end influence the efficacy and toxicity of irinotecan.The main toxicity effects of irinotecan are severe delayed diarrhea and neutropenia.Now,we want to explore the relationship between UGT1A1*28,UGT1A1*6 gene polymorphism and the toxicity of irinotecan based chemotherapy.To a higher degree,we aim to hunt for the molecular marker of the toxicity effects for irinotecan based chemotherapy in gastrointestinal tumor patients.So we can provide the basis for individualized chemotherapy regimens.Methods: We selected 100 advanced gastrointestinal tumor patients confirmed by histopathology after surgery in The First Affiliated Hospital of Luzhou Medical College from May 2014 to October 2015.And all of them were divided into two groups,each group contains fifty cases.One group treated with FOLFIRI,while the other group treated with FOLFOX.We collected 2ml peripheral venous blood from all of them before the first chemotherapy,and then putted them into a refrigerator where the temperature is about-70 ?to frozen the specimen.Finally we tested UGT1A1*28 and UGT1A1*6 gene polymorphism all of them by PCR.Furthermore we observed and recorded the total bilirubin and ALT,AST level before chemotherapy and toxicity reactions caused by chemotherapy all of them contained in our experiment.In the end,we analysis the relationship between UGT1A1*28,UGT1A1*6 gene polymorphism and the toxicity reaction of chemotherapy,the total bilirubin,ALT,AST level before chemotherapy by statistical methods.Results:All of one hundred cases,seventy-seven patients with the wild type UGT1A1*28(TA)6/(TA)6,total bilirubin level before chemotherapy was14.1�17.1umol/L.AST:14.36�17.01U/L,ALT:13.90�17.60U/L.twenty-three cases with the heterozygous mutant type UGT1A1*28(TA)6/(TA)7 and homozygous mutant UGT1A1*28(TA)7/(TA)7,total bilirubin level before chemotherapy was:13.9�5.9umol/L,AST:14.09�4.96U/L,ALT:13.70�5.63U/L.There are no difference between the two groups.For the UGT1A1*6 gene polymorphism,fifty-nine patients with wild type UGT1A1*6(G/G),the total bilirubin level before chemotherapy was:15.0�19.4umol/l.AST:15.64�19.22 U/L,ALT:15.24�19.90U/L.While the hybrid mutant UGT1A1*6(G/A)and homozygous mutant UGT1A1*6(A/A),a total of forty-one cases.The total bilirubin level was:12.6�5.3umol/L and AST:12.37�4.60U/L,ALT:11.85�4.92 U/L.There are no difference between the two groups also.The UGT1A1*6 mutation rate is higher than UGT1A1*28,P<0.01.In the group treated with FOLFIRI,eight patients suffered delayed diarrhea above ?level and three cases suffered peripheral nerve injury.comparing to this,In the group treated with FOLFOX,twelve patients endured peripheral nerve injury,and only one case suffered delayed diarrhea above ?level.Only one case occurred anemia above level in each group.And we did not found above level magnitude ? ?leukopenia,neutropenia and thrombocytopenia in the two groups.Compering with the group treated with FOLFOX,the patients treated with FOLFIRI are apt to occur delayed diarrhea above ?level.while the FOLFOX group's main toxicity reaction is peripheral nerve damage.In the group treated with FOLFIRI,Thirty cases with wild type UGT1A1*6(G/G),among of them,one case occurred severe delayed diarrhea.Twenty patients with hybrid mutant UGT1A1*6(G/A)and homozygous mutant UGT1A1*6(A/A),seven cases of them suffered severe delayed diarrhea.The difference between the two groups is significant,P<0.05.For the UGT1A1*28 gene polymorphism in the group of FOLFIRI.thirty-nine cases with wild type UGT1A1*28(TA)6/(TA)6,among this patients,three of them occurred severe delayed diarrhea.While eleven cases with heterozygous mutant type UGT1A1*28(TA)6/(TA)7 and homozygous mutant UGT1A1*28(TA)7/(TA)7,five of them suffered delayed diarrhea above ?level,P<0.05.Conclusion:The main serious toxicity reaction of the group of FOLFIRI is delayed diarrhea above level.UGT1A1*6 gene single nucleotide mutation ?frequency is higher than the UGT1A1*28.The patients with UGT1A1*28 and UGT1A1*6 gene mutations are easy to suffer from severe delayed diarrhea when they are treated with CPT-11.There was not relationship between total bilirubin,AST,ALT level before chemotherapy and UGT1A1*28,UGT1A1*6.And UGT1A1*28 and UGT1A1*6 gene mutations may not make total bilirubin,AST and ALT level rising also.The last,UGT1A1*28 and UGT1A1*6 gene can be used as the molecular markers to predict the delayed diarrhea above level before use the irino? tecan-based chemotherapy.