IN-VITRO AND IN-VIVO INTERACTION BETWEEN CISPLATIN AND TOPOTECAN IN OVARIAN-CARCINOMA SYSTEMS

Topotecan, a camptothecin analogue, is a specific inhibitor of topoiso merase I approved for use in the treatment of patients with refractory ovarian carcinoma. The drug's mechanism of action suggests a potentia l efficacy of drug combinations incorporating DNA-damaging agents. In an attempt better to define a rational basis for drug combination we e xamined the effect of topotecan on the cytotoxicity and antitumor acti vity of cisplatin in an ovarian carcinoma system growing in vitro and in vivo as a tumor xenograft. The in vitro cell system included a cisp latin-sensitive cell line, IGROV-1, and a cisplatin-resistant subline, IGROV-1/Pt0.5, which is characterized by p53 mutation and loss of nor mal function of the wild-type gene of the parental cell line. This cel l system was chosen since the cell sensitivity to DNA-damaging agents appears to be dependent on p53 gene status. Cytotoxicity was assessed by the growth inhibition assay using different schedules: (a) a l-h pe riod of cisplatin exposure followed by a 24-h topotecan treatment and (b) a l-h period of simultaneous exposure to cisplatin and topotecan. In the case of the sequential schedule, an additive interaction was ob served in IGROV-1 and IGROV-1/Pt0.5 cells. When the simultaneous sched ule was used, a synergistic interaction, more evident for the cisplati n-sensitive cells, was found. On the basis of these observations at a cellular level, the effect of concomitant administration of the two dr ugs (i.e., the most favorable schedule) was studied in the IGROV-1 tum or xenograft, which is moderately responsive to cisplatin and topoteca n. Suboptimal doses of each drug (with a low dose of topotecan, 5.1 mg /kg) achieved an antitumor effect comparable with or superior to that of the optimal dose of a single treatment (tumor weight inhibition, 60 %), thus indicating a pharmacological advantage of the combination ove r the single treatment. However, an increase in the topotecan dose (7. 1 mg/kg) was associated with an evident increase in the toxicity of th e combination, thereby suggesting that the drug interaction was not tu mor-specific. Although the molecular basis of the drug interaction is not clear, it is likely that inhibition of topoisomerase I affects the ability of cells to repair cisplatin adducts. Such findings may have pharmacological implications since they suggest the potential clinical interest of topoisomerase I inhibitors in combination with cisplatin.