Pathophysiological Effects of Vascular Endothelial Growth Factor Receptor-2-Blocking Antibody plus Fractionated Radiotherapy on Murine Mammary Tumors

Abstract

Although clinical trials of antiangiogenic strategies have been disappointing when administered as single agents, such approaches can play an important role in cancer treatment when combined with conventional therapies. Previous studies have shown that DC101, an antiangiogenic monoclonal antibody against vascular endothelial growth factor receptor-2, can produce significant growth inhibition in spontaneous and transplanted tumors but can also induce substantial hypoxia. Because DC101 appears to potentiate radiotherapy in some tumors, the present studies were undertaken to characterize pathophysiological changes following combined therapy and to determine whether radioresponse is enhanced despite the induction of hypoxia. MCa-4 and MCa-35 mammary carcinomas were treated with: (a) DC101; (b) 5 × 6 Gy radiation fractions; or (c) the combination. Image analysis of frozen tumor sections was used to quantitate: (a) hypoxia; (b) spacing of total and perfused blood vessels; and (c) endothelial and tumor cell apoptosis. For MCa-4, combination treatment schedules produced significant and prolonged delays in tumor growth, whereas single-modality treatments had minor effects. For MCa-35, radiation or the combination led to equivalent growth inhibition. In all tumors, hypoxia increased markedly after either radiation or DC101 alone. Although combination therapy produced no immediate pathophysiological changes, hypoxia ultimately increased after cessation of therapy. Preferential increases in endothelial apoptosis following combination treatment suggest that in addition to blocking tumor angiogenesis, DC101 enhances radiotherapy by specifically sensitizing endothelial cells, leading to degeneration of newly formed blood vessels.