Quantification of endothelial cell-targeted anti-Bcl-2 therapy and its suppression of tumor growth and vascularization.
Proapoptotic and antiapoptotic proteins in the Bcl family are key regulators of programmed cell death. It is the interaction between these molecules that determines cellular response to apoptotic signals, making them attractive targets for therapeutic intervention. In recent experiments designed to study tumor angiogenesis, Bcl-2 upregulation in endothelial cells was shown to be a critical mediator of vascular development. In this article, we develop a mathematical model that explicitly incorporates the response of endothelial cells to variations in proapoptotic and antiapoptotic proteins in the Bcl family, as well as the administration of specific antiangiogenic therapies targeted against Bcl-2. The model is validated by comparing its predictions to in vitro experimental data that reports microvessel density prior to and following the administration of 0.05 to 5.0 micromol/L of BL193, a promising small molecule inhibitor of Bcl-2. Numerical simulations of in vivo treatment of tumors predict the existence of a threshold for the amount of therapy required for successful treatment and quantify how this threshold varies with the stage of tumor growth. Furthermore, the model shows how rapidly the least effective dosage of BL193 decreases if an even moderately better inhibitor of Bcl-2 is used and predicts that increasing cell wall permeability of endothelial cells to BL193 does not significantly affect this threshold. A critical challenge of experimental therapeutics for cancer is to decide which drugs are the best candidates for clinical trials. These results underscore the potential of mathematical modeling to guide the development of novel antiangiogenic therapies and to direct drug design.
Jain
Harsh Vardhan
HV
Frankfurt Institute for Advanced Studies, Johann Wolfgang Goethe University, Frankfurt am Main, Germany.
Nör
Jacques Eduardo
JE
Jackson
Trachette Levon
TL
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D015195:Drug Design; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000098:blood supply* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D055503:Protein Multimerization; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D051025:bcl-Associated Death Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D051025:bcl-Associated Death Protein