Potentiation of Prostate Cancer Radiotherapy using Combined Antiangiogenic and Antitumor Therapies

摘要

The focus of this grant period was to delineate the effects of monotherapies or combinations of radiotherapy and AG-013736 (a multiple angiogenic receptor inhibitor) on vascular maturity and function, based on perfusion and hypoxia indices as well as pericyte coverage. In 3 major experiments, 250 tumors were frozen for immunohistochemical staining and image analysis. Almost complete growth inhibition was observed for the combined therapy. Total and perfused vessel counts were significantly decreased, but overall hypoxia was also increased in comparison to volume-matched controls. Although pericyte coverage increased with therapy, dissociated PDGFR+ cells also increased. These findings could be explained by either selective vessel ablation or pericyte recruitment, but clearly indicate that a normalization' of vessels into a more efficiently functioning network is not occurring in response to these specific combined treatments. Ongoing studies are expanding these studies into PC-3 tumor models, and specifically evaluating the effects of alternative scheduling.