Dual-Action Combination Therapy Enhances Angiogenesis while Reducing Tumor Growth and Spread

• Published in: Cancer cell Vol. 27; no. 1; pp. 123 - 137
• Main Authors: Wong, Ping-Pui, Demircioglu, Fevzi, Ghazaly, Essam, Alrawashdeh, Wasfi, Stratford, Michael R.L., Scudamore, Cheryl L., Cereser, Biancastella, Crnogorac-Jurcevic, Tatjana, McDonald, Stuart, Elia, George, Hagemann, Thorsten, Kocher, Hemant M., Hodivala-Dilke, Kairbaan M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.01.2015
• Subjects: Animals; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - therapeutic use; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Lewis Lung - drug therapy; Carcinoma, Lewis Lung - pathology; Cell Line, Tumor; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Deoxycytidine - therapeutic use; Drug Synergism; Gemcitabine; Humans; Lung - blood supply; Lung - pathology; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Neovascularization, Pathologic - drug therapy; Pancreas - blood supply; Pancreas - pathology; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - pathology; Snake Venoms - administration & dosage; Snake Venoms - therapeutic use; Verapamil - administration & dosage; Verapamil - therapeutic use
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2014.10.015

Increasing chemotherapy delivery to tumors, while enhancing drug uptake and reducing side effects, is a primary goal of cancer research. In mouse and human cancer models in vivo, we show that coadministration of low-dose Cilengitide and Verapamil increases tumor angiogenesis, leakiness, blood flow, and Gemcitabine delivery. This approach reduces tumor growth, metastasis, and minimizes side effects while extending survival. At a molecular level, this strategy alters Gemcitabine transporter and metabolizing enzyme expression levels, enhancing the potency of Gemcitabine within tumor cells in vivo and in vitro. Thus, the dual action of low-dose Cilengitide, in vessels and tumor cells, improves chemotherapy efficacy. Overall, our data demonstrate that vascular promotion therapy is a means to improve cancer treatment. •Vascular promotion is distinct from antiangiogenesis and vascular normalization•Vascular promotion enhances tumor angiogenesis, flow, leakiness, and drug delivery•Vascular promotion reduces tumor growth and metastasis while extending survival•Low-dose Cilengitide enhances Gemcitabine uptake and metabolism within tumor cells Wong et al. demonstrates the efficacy of vascular promotion therapy, which is distinct from antiangiogenesis and vascular normalization. Coadministration of low-dose cilengitide and verapamil enhances tumor angiogenesis and gemcitabine delivery, resulting in reduced tumor growth and metastasis.