Tumors depend on neovascularization, and inhibiting angiogenesis is emerging as a major tumor treatment modality. A number of inhibitors are in clinical trials, powerful endogenous inhibitors have been discovered, and the search for additional inhibitors is proceeding worldwide. To help rationalize experiments and optimize future clinical trials, it is important to quantify angiogenic inhibitor effectiveness. However, rather than directly targeting tumor cells, many important anti-angiogenic agents target endothelial cells, perturbing the tumor indirectly. The concomitant time delay in tumor response, together with the fact that the treatments involve repeated dose fractions, means that to quantify inhibitor effectiveness, some mathematical model of tumor growth, implicit or explicit, is needed. This application proposes that effectiveness of angiogenic inhibitors be quantified in terms of carrying capacity, a very widely used model quantity specifying the maximum sustainable tumor size within the current limitations of the host environment. Mathematical models involving dynamic carrying capacity, increasing as the tumor induces angiogenesis or decreasing due to angiogenic inhibitors, will be used, analyzing ongoing murine experiments and pending experiments on spontaneous canine tumors in the laboratory of J. Folkman. Preliminary studies have given a numerical inhibitor effectiveness index, based on fractional decrease of carrying capacity, for TNP-470, angiostatin, and endostatin in the murine model. The project will obtain this index for additional sites, inhibitors, doses, and combinations. It will test the results for robustness and make the following significant and novel applications: (1) Ordering inhibitors numerically according to effectiveness; (2) investigating inhibitor dose-response curves for linearity; and (3) using a numerical, super-additivity criterion for synergism to analyze quantitatively whether the standard chemotherapeutic paradigm, that combinations of different agents are usually preferable to single agents, applies to angiogenic inhibitors. As a check on the mathematical modeling, and to deepen quantitative understanding of carrying capacity, digitized automated imaging of time-dependent intratumor microvessel density after inhibitor exposure will be performed on tumor sections supplied by the Folkman laboratory, testing for positive correlations with calculated carrying capacity.
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