Topotecan and Doxorubicin Combination to Treat Recurrent Ovarian Cancer: The Influence of Drug Exposure Time and Delivery Systems to Achieve Optimum Therapeutic Activity
Menée à l'aide de modèles murins, cette étude évalue l'activité antitumorale d'un traitement combinant le topotecan et une formulation liposomale de la doxorubicine pour le traitement d'un cancer de l'ovaire
Purpose: To provide proof-of-concept data to support use of Doxil–liposomal topotecan (Topophore C) combinations to treat ovarian cancer. Experimental Design: ES-2, OVCAR-3, and SKOV-3 ovarian cancer cell lines were treated with doxorubicin–topotecan combinations by exposing the cells to drugs from 1 to 72 hours. Pharmacokinetic analysis was conducted following administration of liposomal formulations of these drugs alone and in combination. Efficacy assessments were completed in ES-2 and SKOV-3 ovarian cancer models. Results: On the basis of drug doses capable of achieving 50% reduction in cell viability over 72 hours, doxorubicin–topotecan combinations were additive in SKOV-3 but highly synergistic in ES-2 and OVCAR-3 cells. Favorable drug–drug interactions increased with increased drug exposure time. Topophore C pharmacokinetic remained unaffected when co-administered with Doxil. In the ES-2 model, Doxil at maximum tolerated dose (MTD 7.5 mg/kg) in combination with free topotecan (MTD 15 mg/kg) did not enhance median survival time (MST) over that achieved with topotecan alone. In contrast, MST was increased to 52 days with combination of Topophore C (MTD 2.5 mg/kg) and Doxil (7.5 mg/kg) compared with untreated animals (MST 18 days) or those treated with Topophore C alone (MTD 5 mg/kg, MST 40 days). In the SKOV-3 model, combination treatments showed better therapeutic efficacy than the individual drugs. Conclusions: Topotecan–doxorubicin combinations produced additive or synergistic effects which were best achieved when the tumor cells were exposed to drugs over extended time. Doxil–Topophore C combinations are therapeutically superior as judged in two ovarian cancer models. Clin Cancer Res; 1–13. ©2012 AACR.