APOPTOSIS AS A DETERMINANT OF TUMOR SENSITIVITY TO TOPOTECAN IN HUMANOVARIAN-TUMORS - PRECLINICAL IN-VITRO IN-VIVO STUDIES

Preclinical and clinical studies have documented the pharmacological i nterest in camptothecin derivatives in the treatment of resistant tumo rs, In particular, topotecan, a water-soluble derivative, exhibited pr omising activity in pretreated ovarian carcinoma, The present study in vestigated the pattern of tumor response in two human ovarian carcinom a xenografts and in their cisplatin-resistant sublines characterized b y different mechanisms of drug resistance, In IGROV-1/Pt1 cells, cispl atin resistance has been ascribed to a reduced susceptibility to apopt osis as a consequence of p53 mutation and inactivation of its function , In the A2780 cisplatin-resistant subline, which retained the wild-ty pe p53 gene status, the development of resistance has been possibly re lated to increased cell ability to repair drug-induced DNA damage, The in vivo results of the present study showed that topotecan could over come the resistance in A2780/CP but not in IGROV-1/Pt1 tumor xenograft s, 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 pro gression, 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 cur rent 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 cel l response to topoisomerase inhibitors.