Theoretical investigation of the efficacy of antiangiogenic drugs combined to chemotherapy in xenografted mice

J Theor Biol. 2013 Mar 7;320:86-99. doi: 10.1016/j.jtbi.2012.12.013. Epub 2012 Dec 21.

Abstract

Antiangiogenic drugs were developed with the aim to inhibit the formation of intratumoral blood vessels and in consequence the growth of solid tumors. As these drugs are generally combined with classical cytotoxic drugs in the treatment of cancer patients, finding the optimal combinations remains a complex challenge due to possible interactions of the antiangiogenic compound with the hemodynamic property of the treated tumor. To analyze this problem, we developed a multi-scale model of vascular tumor growth combining a molecular model of VEGF signaling pathways and a tissue model of the tumor expansion including the dynamics of cellular and tissue processes of tumor growth and response to treatments. We addressed the potential impact of antiangiogenic drug by defining a new index of vasculature quality which depends on the balance between stable and unstable vessels within the tumor mass. Our goal was to investigate the interactions between a chemotherapy and a antiangiogenic treatment, and, by simulating the model, to identify the optimal delay of chemotherapy delivery after the administration of the antiangiogenic compound. This theoretical analysis could be used in the future to optimize antiangiogenic drug delivery in preclinical settings and to facilitate the translation from preclinical to clinical studies.

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Cytotoxins / pharmacology
  • Humans
  • Mice
  • Models, Biological*
  • Neoplasm Proteins / metabolism
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / pathology
  • Neoplasms, Experimental / physiopathology
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Neovascularization, Pathologic / physiopathology
  • Signal Transduction / drug effects
  • Vascular Endothelial Growth Factor A / metabolism
  • Xenograft Model Antitumor Assays / methods

Substances

  • Angiogenesis Inhibitors
  • Cytotoxins
  • Neoplasm Proteins
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse