Value of TopoⅡα, GST-π and P-gp in Predicting Chemotherapeutic Response and Prognosis of Ovarian Cancer in vivo and in vitro
-
摘要: 目的 研究TopoⅡα、GST-π、P-gp在卵巢癌耐药中的作用及其对化疗反应及预后的预测价值。方法免疫组织化学SP法检测TopoⅡα、GST-π、MDR-1/P-gp在80例上皮性卵巢癌组织中的表达,分析它们与化疗反应及预后的关系;RNA干扰封闭GST-π、MDR-1/P-gp在人卵巢癌耐药细胞中的表达,检测其逆转细胞耐药的可能性。结果TopoⅡα阴性和阳性患者的化疗反应无差异。GST-π阴性患者的化疗疗效显著优于阳性者(P=0.009);P-gp阴性患者也较阳性者疗效好,但差异无统计学意义(P=0.059)。尽管Log-rank test显示 GST-π 或P-gp阴性患者的生存时间显著长于相应指标阳性患者,但Cox分析并未指示两者为独立预后因素 (P=0.682;P=0.101)。根据GST-π、P-gp的共同表达情况进一步分组分析显示,两者共同阴性的患者化疗有效率100%、85.7%生存至末次随访,GST-π、P-gp共同阴性预示较好的化疗反应及预后(P=0.012;P=0.000) 。体外实验显示,卵巢癌耐药细胞对多种化疗药物敏感度降低,同时GST-π、MDR-1/P-gp mRNA表达增高。结论GST-π及MDR-1/ P-gp在卵巢癌耐药中具重要作用,GST-π 或P-gp单独预测化疗反应及预后的效用有限, 联合检测可提供较高临床价值，封闭两者表达可一定程度逆转卵巢癌细胞的耐药性。
-
关键词:
- 多药耐药 /
- 卵巢癌 /
- 谷胱甘肽-S-转移酶-πP-糖蛋白 /
- 拓扑异构酶Ⅱ&alpha
Abstract: Objective To assess the role of TopoⅡα,GST-π and P-gp in drug-resistance of ovarian cancer and their value as predictors of chemotherapeutic response and prognosis. Methods The expression of GST-π,P-gp and TopoⅡ α in the surgical specimens were detected by immunohistochemistry and their relationship with the chemotherapeutic response and prognosis of the patients were analyzed.The expression of GST-π and MDR-1/P-gp in human ovarian cancer cells was silenced by RNA:to evaluate the feasibility of reversal MDR phenotype in the cells. ResultsChemotherapeutic response was no difference with negative TopoⅡα and positive.Chemotherapeutic response was more favorable in patients with negative GST-π than in those with positive expression (P=0.009).Similar trend occurred with P-gp,though the difference was not significant (P=0.059).Although log-rank test showed a longer survival in patients with negative GST-π or P-gp (P=0.012;P=0.000),Cox hazard analysis did not indicate they could be regarded as prognostic predictors (P=0.682;P=0.101).However,when their co-expression status was taken into account,it was found that 100.0% patients with co-negative GST-π/P-gp responded well to chemotherapy and 85.7% patients were still alive until the evaluation.Co-negative GST-π /P-gp presented better chemotherapeutic response and prognosis (P=0.001;P=0.000).Furthermore,decreased drug sensitivity accompanied with overexpressed GST-π and P-gp level was found in MDR ovarian cancer cell lines. Conclusion GST-π and P-gp are involved in the forming of MDR in ovarian cancer.The reliability of MDR-1 and GST-π alone as indicators of chemotherapeutic response and prognosis is limited,and co-detection of their expression may provide a higher predictive value. After silencing the expression of GST-π and P-gp by RNAi,the drug sensitivity of the MDR cells were increased. -
-
[1] Vaughan S,Coward JI,Bast RC Jr,et al.Rethinking ovarian cancer:recommendations for improvingoutcomes[J].Nat Rev Cancer,2011,11(10):719-25. [2] Bookman MA.Developmental chemotherapy and management of recurrent ovarian cancer[J].J ClinOncol,2003,21(10 suppl):149s-67s. [3] Modesitt SC,Jazaeri AA.Recurrent epithelial ovarian cancer:Pharmacotherapy and novel therapeutics[J].Expert Opin Pharmacother,2007,8(14):2293-305. [4] Gottesman MM.Mechanisms of cancer drug resistance[J].Annu Rev Med,2002,53:615-27. [5] Penson RT,Oliva E,Skates SJ,et al.Expression of multidrug resistance-1 protein inverselycorrelates with paclitaxel response and survival in ovarian cancer patients:a study in serial samples[J].Gynecol Oncol,2004,93(1):98-106. [6] Lu D,Shi HC,Wang ZX,et al.Multidrug resistance-associated biomarkers PGP,GST-pi,Topo-II and LRPasprognostic factors in primary ovarian carcinoma[J].Br J Biomed Sci,2011,68(2):69-74. [7] Van der Zee AG,van Ommen B,Meijer C,et al.Glutathione S-transferase activity and isoenzymecomposition in benign ovarian tumours,untreated malignant ovarian tumours,and malignant ovariantumours after platinum/cyclophosphamide chemotherapy[J].Br J Cancer,1992,66(5):930-6. [8] Lu YB,Zhang L,Chen Y,et al.Topoisomerase expression and clinical significance in ovarian tumortissue[J].Yunnan Yi Yao,2001,22(2):84-6.[卢玉波,张林,陈芸,等.卵巢肿瘤组织中拓扑异构酶的表达及其临床意义[J].云南医药,2001,22(2):84-6.] [9] Koshiyama M,Fujii H,Kinezaki M,et al.Correlation between Topo II alpha expression andchemosensitivity testing for Topo II-targeting drugs in gynaecological carcinomas[J].AnticancerRes,2001,21(2A):905-10. [10] Khalifa MA,Abdoh AA,Mannel RS,et al.P-glycoprotein as a prognostic indicator in pre- andpostchemotherapy ovarian adenocarcinoma[J].Int J Gynecol Pathol,1997,16 (1):69-75. [11] Ferrandina G,Petrillo M,Carbone A,et al.Prognostic role of topoisomerase-IIalpha in advancedovarian cancer patients[J].Br J Cancer,2008,98(12):1910-15. [12] Saip P,Tuzlali S,Demir K,et al.Value of glutathion-S transferase pi as a prognostic factor inepithelial ovarian carcinoma[J].Eur J Gynaecol Oncol,2005,26(1):90-4. [13] Ikeda K,Sakai K,Yamamoto R,et al.Multivariate analysis for prognostic significance of histologicsubtype,GST-pi,MDR-1,and p53 in stages II-IV ovarian cancer[J].Int J Gynecol Cancer,2003,13(6):776-84. [14] Ozalp SS,Yalcin OT,Tanir M,et al.Multidrug resistance gene-1 (Pgp) expression in epithelialovarian malignancies[J].Eur J Gynaecol Oncol,2002,23(4):337-40. [15] Zhang T,Guan M,Jin HY,et al.Reversal of multidrug resistance by small interfering double-stranded RNAs in ovarian cancer cells[J].Gynecol Oncol,2005,97(2):501-7.
计量
- 文章访问数: 2156
- HTML全文浏览量: 21
- PDF下载量: 529
下载:
