药物不良反应杂志
藥物不良反應雜誌
약물불량반응잡지
ADVERSE DRUG REACTIONS JOURNAL
2013年
3期
136-140
,共5页
宋丽雪%王金萍%高昕%许卫东
宋麗雪%王金萍%高昕%許衛東
송려설%왕금평%고흔%허위동
UGT1A%基因突变%伊立替康%迟发性腹泻%白细胞和(或)粒细胞减少
UGT1A%基因突變%伊立替康%遲髮性腹瀉%白細胞和(或)粒細胞減少
UGT1A%기인돌변%이립체강%지발성복사%백세포화(혹)립세포감소
UGT1A%Gene mutation%Irinotecan%Delayed diarrhea%Neutropenia
目的 探讨尿苷二磷酸葡糖醛酸基转移酶1家族肽A(UGT1A)基因多态性与抗肿瘤药伊立替康所致不良反应的相关性,为肿瘤患者个体化用药提供参考. 方法 研究对象为233名健康志愿者和196例应用伊立替康治疗的肿瘤患者.健康志愿者中男性169名,女性64名；平均年龄(25±5)岁.肿瘤患者中肠癌92例,宫颈癌45例,卵巢上皮细胞癌59例；男性54例,女性142例；平均年龄(61±19)岁.采用焦磷酸测序法对2组受试者进行UGT1A1*6、UGT1A1* 28、UGT1A3*1、UGT1A3*2、UGT1A3*3、UGT1A3*4和UGT1A9* 22基因多态性检测,比较2组受试者UGT1A基因型突变频率,比较不同UGT1A基因型患者迟发性腹泻和白细胞和/或中性粒细胞减少发生率,采用Logistic回归方法分析伊立替康致不良反应的危险因素,结果以相对危险度(OR)及95％置信区间表示. 结果 肿瘤患者UGT1A3*2基因型突变频率明显低于健康志愿者(50.3％比68.5％,P=0.014),而UGT1A3*3基因型突变频率明显高于健康志愿者(26.0％比6.2％,P=0.001).196例肿瘤患者Ⅱ～Ⅳ度迟发性腹泻发生率为48.5％(95例),Ⅲ～Ⅳ度迟发性腹泻发生率为11.2％(22例)；Ⅲ～Ⅳ度中性粒细胞减少发生率为49.0％(96例).UGT1A1*28位点野生型纯合子(WW)基因型携带者Ⅱ～Ⅳ度和Ⅲ～Ⅳ度迟发性腹泻发生率均明显低于突变型杂合子(WM)+突变型纯合子(MM)基因型携带者[Ⅱ～Ⅳ度:40.4％(57/141)比69.1％(38/55),P=0.006；Ⅲ～Ⅳ度:5.7％(8/141)比25.5％(14/55),P=0.001]；UGT1A9* 22位点WW基因型携带者Ⅱ～Ⅳ度迟发型腹泻发生率明显低于WM+ MM基因型携带者[26.2％(17/65)比47.6％(40/84),P=0.006;26.2％(17/65)比51.1％ (24/47),P=0.0057],未发现不同基因型患者之间Ⅲ～Ⅳ度中性粒细胞减少发生率差异存在统计学意义.Logistic回归分析显示UGT1A基因型与迟发性腹泻的发生相关(OR=5.657,95％置信区间为4.782～ 7.245,P=0.039). 结论 UGT1A1*28和UGT1A9*22基因多态性可增加伊立替康所致迟发性腹泻的风险.
目的 探討尿苷二燐痠葡糖醛痠基轉移酶1傢族肽A(UGT1A)基因多態性與抗腫瘤藥伊立替康所緻不良反應的相關性,為腫瘤患者箇體化用藥提供參攷. 方法 研究對象為233名健康誌願者和196例應用伊立替康治療的腫瘤患者.健康誌願者中男性169名,女性64名；平均年齡(25±5)歲.腫瘤患者中腸癌92例,宮頸癌45例,卵巢上皮細胞癌59例；男性54例,女性142例；平均年齡(61±19)歲.採用焦燐痠測序法對2組受試者進行UGT1A1*6、UGT1A1* 28、UGT1A3*1、UGT1A3*2、UGT1A3*3、UGT1A3*4和UGT1A9* 22基因多態性檢測,比較2組受試者UGT1A基因型突變頻率,比較不同UGT1A基因型患者遲髮性腹瀉和白細胞和/或中性粒細胞減少髮生率,採用Logistic迴歸方法分析伊立替康緻不良反應的危險因素,結果以相對危險度(OR)及95％置信區間錶示. 結果 腫瘤患者UGT1A3*2基因型突變頻率明顯低于健康誌願者(50.3％比68.5％,P=0.014),而UGT1A3*3基因型突變頻率明顯高于健康誌願者(26.0％比6.2％,P=0.001).196例腫瘤患者Ⅱ～Ⅳ度遲髮性腹瀉髮生率為48.5％(95例),Ⅲ～Ⅳ度遲髮性腹瀉髮生率為11.2％(22例)；Ⅲ～Ⅳ度中性粒細胞減少髮生率為49.0％(96例).UGT1A1*28位點野生型純閤子(WW)基因型攜帶者Ⅱ～Ⅳ度和Ⅲ～Ⅳ度遲髮性腹瀉髮生率均明顯低于突變型雜閤子(WM)+突變型純閤子(MM)基因型攜帶者[Ⅱ～Ⅳ度:40.4％(57/141)比69.1％(38/55),P=0.006；Ⅲ～Ⅳ度:5.7％(8/141)比25.5％(14/55),P=0.001]；UGT1A9* 22位點WW基因型攜帶者Ⅱ～Ⅳ度遲髮型腹瀉髮生率明顯低于WM+ MM基因型攜帶者[26.2％(17/65)比47.6％(40/84),P=0.006;26.2％(17/65)比51.1％ (24/47),P=0.0057],未髮現不同基因型患者之間Ⅲ～Ⅳ度中性粒細胞減少髮生率差異存在統計學意義.Logistic迴歸分析顯示UGT1A基因型與遲髮性腹瀉的髮生相關(OR=5.657,95％置信區間為4.782～ 7.245,P=0.039). 結論 UGT1A1*28和UGT1A9*22基因多態性可增加伊立替康所緻遲髮性腹瀉的風險.
목적 탐토뇨감이린산포당철산기전이매1가족태A(UGT1A)기인다태성여항종류약이립체강소치불량반응적상관성,위종류환자개체화용약제공삼고. 방법 연구대상위233명건강지원자화196례응용이립체강치료적종류환자.건강지원자중남성169명,녀성64명；평균년령(25±5)세.종류환자중장암92례,궁경암45례,란소상피세포암59례；남성54례,녀성142례；평균년령(61±19)세.채용초린산측서법대2조수시자진행UGT1A1*6、UGT1A1* 28、UGT1A3*1、UGT1A3*2、UGT1A3*3、UGT1A3*4화UGT1A9* 22기인다태성검측,비교2조수시자UGT1A기인형돌변빈솔,비교불동UGT1A기인형환자지발성복사화백세포화/혹중성립세포감소발생솔,채용Logistic회귀방법분석이립체강치불량반응적위험인소,결과이상대위험도(OR)급95％치신구간표시. 결과 종류환자UGT1A3*2기인형돌변빈솔명현저우건강지원자(50.3％비68.5％,P=0.014),이UGT1A3*3기인형돌변빈솔명현고우건강지원자(26.0％비6.2％,P=0.001).196례종류환자Ⅱ～Ⅳ도지발성복사발생솔위48.5％(95례),Ⅲ～Ⅳ도지발성복사발생솔위11.2％(22례)；Ⅲ～Ⅳ도중성립세포감소발생솔위49.0％(96례).UGT1A1*28위점야생형순합자(WW)기인형휴대자Ⅱ～Ⅳ도화Ⅲ～Ⅳ도지발성복사발생솔균명현저우돌변형잡합자(WM)+돌변형순합자(MM)기인형휴대자[Ⅱ～Ⅳ도:40.4％(57/141)비69.1％(38/55),P=0.006；Ⅲ～Ⅳ도:5.7％(8/141)비25.5％(14/55),P=0.001]；UGT1A9* 22위점WW기인형휴대자Ⅱ～Ⅳ도지발형복사발생솔명현저우WM+ MM기인형휴대자[26.2％(17/65)비47.6％(40/84),P=0.006;26.2％(17/65)비51.1％ (24/47),P=0.0057],미발현불동기인형환자지간Ⅲ～Ⅳ도중성립세포감소발생솔차이존재통계학의의.Logistic회귀분석현시UGT1A기인형여지발성복사적발생상관(OR=5.657,95％치신구간위4.782～ 7.245,P=0.039). 결론 UGT1A1*28화UGT1A9*22기인다태성가증가이립체강소치지발성복사적풍험.
Objective To explore the correlation between UDP-glucuronosyltransferases 1 family polypeptide A (UGT1A)gene polymorphism and the adverse reactions induced by antineoplastic agent irinotecan,in order to provide a reference of individual therapy for patients with tumor.Methods The subjects were 233 healthy volunteers and 196 patients with tumor received irinotecan.The healthy volunteers comprised 169 male and 64 female with mean age of (25 ± 5) years.Of the 196 patients with tumor,92 had carcinoma of rectum,45 had cervical carcinoma,and 59 had epithelial ovarian cancer.They comprised 54 male and 142 female with a mean age of (61 ± 19) years.The gene polymorphism of UGT1A1 * 6,UGT1A1 * 28,UGT1A3 * 1,UGT1A3 * 2,UGT1A3 * 3,UGT1A3 * 4,and UGT1A9 * 22 were detected by pyrosequencing.The genotypic mutation frequency of UGT1A in subjects between the 2 groups were compared.The incidences of delayed diarrhea and neutropenia in patients with different UGT1A genotypes were compared.The risk factors of adverse reactions due to irinotecan were analyzed by Logistic regression analysis.The results were represented by odds ratio (OR) and 95％ confidence interval (CI).Results The UGT1 A3 * 2 genotypic mutation frequency in the patients with tumor was significantly lower than that in the healthy volunteers (50.3％ vs.68.5％,P =0.014),and the UGT1A3 * 3 genotypic mutation frequency in the patients with tumor was significantly higher than that in the healthy volunteers (26.0％ vs.6.2％,P =0.001).The incidences of level Ⅱ-Ⅳ and Ⅲ-Ⅳ delayed diarrhea,and the neutropenia were 48.5％ (95 cases),11.2％ (22 cases),and 49.0％ (96 cases) in 196 patients with tumor,respectively.The incidences of level Ⅱ-Ⅳ and Ⅲ-Ⅳ delayed diarrhea in UGT1A1 * 28 wild type (WW) carriers were significantly lower than those in the mutant heterozygote (WM) + homozygous mutant (MM) genotype carriers [Ⅱ-Ⅳ:40.4％ (57/141)vs.69.1％ (38/55),P =0.006; Ⅲ-Ⅳ:5.7％ (8/141) vs.25.5％ (14/55),P =0.001].The incidences of level Ⅱ-Ⅳ delayed diarrhea in UGT1 A9 * 22 (WW) carriers were significantly lower than those in the WM and MM carriers [26.2％ (17/65)vs.47.6％ (40/84),P =0.006 ;26.2％ (17/65) vs.51.1％ (24/47) P =0.0057].There were no statistical differences in incidences of level Ⅲ-Ⅳ neutropenia among the patients with different genotypes.Logistic regression analysis showed that UGT1A genotype was related to the delayed diarrhea(OR =5.657,95 ％ CI:4.782-7.245,P =0.039).Conclusion UGT1A1 * 28 and UGT1A9 * 22 gene polymorphism may increase the risk of delayed diarrhea induced by irinotecan.
