We propose to test a novel hypothesis that angiogenesis in non-tumor tissue induced independently of tumor, contributes to the growth of tumor. Thus if a therapeutic intervention to treat tumor induces angiogenesis in adjacent non-tumor tissue, this angiogenesis increases the likelihood of tumor regrowth from residual tumor cells. We propose to test this hypothesis in a model of human glioma in the nude mouse. The anti tumor treatment employed is photodynamic therapy (PDT) using Photofrin as the photosensitizer.
In specific aim A, the angiogenic response of normal brain to PDT is tested and the effects of implantation of tumor in PDT induced angiogenic brain are analyzed. As a logical consequence of experiments performed in specific Aim A, we test the effects of combination treatment of U87 human glioma in the mouse brain using PDT and antiangiogenic agents in specific aim B. We expect that the combination treatment will significantly reduce the rate of tumor regrowth and thereby extend the life of animals compared to the individual treatments. The anti-angiogenic agents employed are antibodies against the vascular endothelial growth factor receptors (VEGFR1 and VEGFR2). If we are correct, that endogenous brain angiogenesis contributes to tumor regrowth, then our study has important implications for the treatment of brain tumor using most forms of anti tumor agents. Thus, the use of a combination anti-angiogenic and direct tumoricidal treatment may translate into improved therapeutic opportunity. ? ?
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