Dual Metronomic Chemotherapy with Nab-Paclitaxel and Topotecan Has Potent Antiangiogenic Activity in Ovarian Cancer. Mol Cancer Ther 2015 Dec;14(12):2677-86
Date
10/31/2015Pubmed ID
26516159Pubmed Central ID
PMC4674355DOI
10.1158/1535-7163.MCT-14-0630Scopus ID
2-s2.0-84958151163 (requires institutional sign-in at Scopus site) 9 CitationsAbstract
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.
Author List
Previs RA, Armaiz-Pena GN, Lin YG, Davis AN, Pradeep S, Dalton HJ, Hansen JM, Merritt WM, Nick AM, Langley RR, Coleman RL, Sood AKAuthor
Sunila Pradeep PhD Associate Professor in the Obstetrics and Gynecology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Administration, MetronomicAlbumins
Angiogenesis Inhibitors
Animals
Antineoplastic Combined Chemotherapy Protocols
Apoptosis
Cell Line, Tumor
Cell Proliferation
Drug Resistance, Neoplasm
Female
Humans
Mice
Neovascularization, Pathologic
Ovarian Neoplasms
Paclitaxel
Topotecan
Xenograft Model Antitumor Assays