Determination of the optimal combination chemotherapy regimen for treatment of platinum-resistant ovarian cancer in nude mouse model

Abstract

Objective. The primary objective of this study was to evaluate the potential to increase the in vivo activity of liposomal doxorubicin when administered in combination with other chemotherapeutic agents such as topotecan, docetaxel, gemcitabine, capecitabine, or celecoxib in an ovarian cancer xenograft mouse model to identify new treatment options for recurrent platinum-sensitive/resistant ovarian cancer. Methods. This was a five-arm study in two xenograft ovarian cancer mouse models, ES-2 (platinum-sensitive), and OVCAR3 (platinumresistant), to evaluate the combination of liposomal doxorubicin with the common chemotherapeutic agents. Each cell line had five mice for each treatment arm, five vehicle control mice, and five liposomal doxorubicin alone control mice. Experiments were done in duplicate. Results. The percentage tumor reduction ranged from 52% to 74.1% for the single-agent treatment arms. Tumor growth inhibition and regression (response) was improved on the combination treatment arms ranging from 76.1% to 100%.We observed increased activity in the liposomal doxorubicin plus topotecan arm, with a 27.3% improvement in response, compared with either agent alone. Conclusions. The addition of liposomal doxorubicin demonstrated increased antitumor activity compared with either agent used alone. The most active combination treatment arm was liposomal doxorubicin with topotecan which is consistent with recent clinical study reports of enhanced activity with the combination of topoisomerase I and topoisomerase II agents. Additional studies are warranted to evaluate the efficacy and safety to optimize the combination of liposomal doxorubicin and topotecan for the treatment of recurrent or refractory ovarian cancer.