Dual-action combination therapy enhances angiogenesis while reducing tumor growth and spread

Cancer Cell. 2015 Jan 12;27(1):123-37. doi: 10.1016/j.ccell.2014.10.015.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • 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

Substances

  • Antimetabolites, Antineoplastic
  • Snake Venoms
  • Deoxycytidine
  • Cilengitide
  • gemcitabine
  • Verapamil