Dual Metronomic Chemotherapy with Nab-Paclitaxel and Topotecan Has Potent Antiangiogenic Activity in Ovarian Cancer

• Published in: Molecular cancer therapeutics 2015-12, Vol.14 (12), p.2677-2686
• Main Authors: Previs, Rebecca A, Armaiz-Pena, Guillermo N, Lin, Yvonne G, Davis, Ashley N, Pradeep, Sunila, Dalton, Heather J, Hansen, Jean M, Merritt, William M, Nick, Alpa M, Langley, Robert R, Coleman, Robert L, Sood, Anil K
• Format: Article
• Language: English
• Subjects: Administration, Metronomic; Albumins - administration & dosage; Angiogenesis Inhibitors - administration & dosage; Animals; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Apoptosis - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Resistance, Neoplasm; Female; Humans; Mice; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - pathology; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - pathology; Paclitaxel - administration & dosage; Topotecan - administration & dosage; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-14-0630

There is growing recognition of the important role of metronomic chemotherapy in cancer treatment. On the basis of their unique antiangiogenic effects, we tested the efficacy of nab-paclitaxel, which stimulates thrombospondin-1, and topotecan, which inhibits hypoxia-inducible factor 1-α, at metronomic dosing for the treatment of ovarian carcinoma. In vitro and in vivo SKOV3ip1, HeyA8, and HeyA8-MDR (taxane-resistant) orthotopic models were used to examine the effects of metronomic nab-paclitaxel and metronomic topotecan. We examined cell proliferation (Ki-67), apoptosis (cleaved caspase-3), and angiogenesis (microvessel density, MVD) in tumors obtained at necropsy. In vivo therapy experiments demonstrated treatment with metronomic nab-paclitaxel alone and in combination with metronomic topotecan resulted in significant reductions in tumor weight (62% in the SKOV3ip1 model, P < 0.01 and 96% in the HeyA8 model, P < 0.03) compared with vehicle (P < 0.01). In the HeyA8-MDR model, metronomic monotherapy with either cytotoxic agent had modest effects on tumor growth, but combination therapy decreased tumor burden by 61% compared with vehicle (P < 0.03). The greatest reduction in MVD (P < 0.05) and proliferation was seen in combination metronomic therapy groups. Combination metronomic therapy resulted in prolonged overall survival in vivo compared with other groups (P < 0.001). Tube formation was significantly inhibited in RF-24 endothelial cells exposed to media conditioned with metronomic nab-paclitaxel alone and media conditioned with combination metronomic nab-paclitaxel and metronomic topotecan. The combination of metronomic nab-paclitaxel and metronomic topotecan offers a novel, highly effective therapeutic approach for ovarian carcinoma that merits further clinical development.