Caserini C, Pratesi G, Tortoreto M, Bedogné B, Carenini N, Supino R, Perego P, Righetti S C, Zunino F
Division of Experimental Oncology B, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy.
Clin Cancer Res. 1997 Jun;3(6):955-61.
Preclinical and clinical studies have documented the pharmacological interest in camptothecin derivatives in the treatment of resistant tumors. In particular, topotecan, a water-soluble derivative, exhibited promising activity in pretreated ovarian carcinoma. The present study investigated the pattern of tumor response in two human ovarian carcinoma xenografts and in their cisplatin-resistant sublines characterized by different mechanisms of drug resistance. In IGROV-1/Pt1 cells, cisplatin resistance has been ascribed to a reduced susceptibility to apoptosis as a consequence of p53 mutation and inactivation of its function. In the A2780 cisplatin-resistant subline, which retained the wild-type p53 gene status, the development of resistance has been possibly related to increased cell ability to repair drug-induced DNA damage. The in vivo results of the present study showed that topotecan could overcome the resistance in A2780/CP but not in IGROV-1/Pt1 tumor xenografts. The pattern of tumor response following in vivo topotecan treatment correlated with drug ability to induce apoptosis but not with its in vitro antiproliferative activity. The antitumor efficacy of topotecan in the four tumors reflected a different cell response to drug-induced DNA damage, as suggested by different perturbations of cell cycle progression. Indeed, only in the subline refractory to topotecan in vivo, IGROV-1/Pt1, did we observe a persistent arrest of the cells in the S-phase, resulting in a cytostatic and not a cytotoxic effect, since a low level of apoptosis was induced by the drug. In conclusion, the current results support that determination of drug-induced apoptosis is a useful predictor of tumor response to topotecan in ovarian carcinomas and suggest that p53 gene status may be a critical determinant of cell response to topoisomerase inhibitors.
临床前和临床研究已证明喜树碱衍生物在治疗耐药肿瘤方面具有药理学研究价值。特别是拓扑替康，一种水溶性衍生物，在预处理的卵巢癌中表现出有前景的活性。本研究调查了两种人卵巢癌异种移植瘤及其具有不同耐药机制的顺铂耐药亚系中的肿瘤反应模式。在IGROV - 1/Pt1细胞中，顺铂耐药归因于p53突变及其功能失活导致对凋亡的敏感性降低。在保留野生型p53基因状态的A2780顺铂耐药亚系中，耐药的发生可能与细胞修复药物诱导的DNA损伤的能力增加有关。本研究的体内结果表明，拓扑替康可以克服A2780/CP中的耐药性，但不能克服IGROV - 1/Pt1肿瘤异种移植瘤中的耐药性。体内拓扑替康治疗后的肿瘤反应模式与药物诱导凋亡的能力相关，而与其体外抗增殖活性无关。拓扑替康在这四种肿瘤中的抗肿瘤疗效反映了细胞对药物诱导的DNA损伤的不同反应，这由细胞周期进程的不同扰动所表明。事实上，只有在体内对拓扑替康耐药的亚系IGROV - 1/Pt1中，我们观察到细胞持续停滞在S期，导致细胞生长抑制而非细胞毒性作用，因为该药物诱导的凋亡水平较低。总之，目前的结果支持确定药物诱导的凋亡是卵巢癌中肿瘤对拓扑替康反应的有用预测指标，并表明p53基因状态可能是细胞对拓扑异构酶抑制剂反应的关键决定因素。
