Combination of vascular endothelial growth factor receptor/platelet-derived growth factor receptor inhibition markedly improves radiation tumor therapy.

摘要: Purpose: Investigations on the combination of radiotherapy with vascular endothelial growth factor (VEGF) and platelet-derived (PDGF) antiangiogenic agents, which has potential to improve clinical outcome in cancer patients. Experimental Design: Here, we analyze combined VEGF (SU5416) PDGF (SU6668) receptor tyrosine kinase inhibition irradiation human endothelium (HUVEC), prostate (PC3), glioblastoma (U87) vitro vivo . Results: Combined signaling resulted enhanced apoptosis, reduced cell proliferation, clonogenic survival as well migration tube formation compared single pathway inhibition. These effects were further by additional irradiation. Likewise, PC3 U87 tumors growing s.c. BALB/c nu/nu mice, dual significantly increased tumor delay versus each monotherapy. Interestingly, radiation at ∼20% dose necessary induce local control exerts similar growth-inhibitory drugs given their maximum effective dose. Addition both mono- dual-antiangiogenic treatment markedly delay. With respect angiogenesis, decreased microvessel density (CD31 count) proliferation (Ki-67 index) all drug-treated groups. Of note, slowly responded better drug treatments than faster-growing tumor. In addition beneficial effect abrogating when radiation, identified here a novel mechanism for escape from damage. We found that induced up-regulation four isoforms (A-D) cells supporting adjacent smooth muscle resulting prosurvival radiation. The SU6668 attenuated this undesirable paracrine effect, may rationalize application increase antitumor effects. Conclusion: A relative low enhances inhibition, suggesting promising regimen remaining an essential element.