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.

Ionizing Radiation Antagonizes Tumor Hypoxia Induced by Antiangiogenic Treatment

“…This observation is consistent with reduced oxygenation in histochemically analyzed tumor sections after treatment with the anti-vascular endothelial growth factor receptor-2 antibody DC101 alone but not in response to combined treatment with irradiation (21). However, our results and the results from Fenton et al are in contradiction to the ''tumor vascular normalization'' concept, which claims that treatment with low doses of angiogenesis inhibitors preferentially targets immature vessels and by that creates a normalization window with improved functionality of the remaining tumor vasculature.…”

“…The FMISO-PET results showed strong correlation with GLUT-1 immunostaining, which was used as an independent approach to assess allograft hypoxia. Thus, FMISO-PET represents a potent method to analyze tumor oxygenation in experimental and clinical settings, to follow treatment responses, and to investigate potential hazards especially of combined treatment modalities (2,21,24). In conclusion, our study has directly investigated in vivo the effects on tumor oxygenation of an antiangiogenic treatment with PTK787, ionizing radiation, or a combination of PTK787 and ionizing radiation.…”

Combination of human plasminogen kringle 5 with ionizing radiation significantly enhances the efficacy of antitumor effect

“…3,4 Several preclinical studies have indicated that antiangiogenic treatment may enhance the antitumor effect of radiotherapy without increasing damage to normal tissues. [5][6][7][8] Angiogenesis plays a key role in tumor progression. It was hypothesized that inhibition of angiogenesis would be an effective strategy to treat human cancer, and an active search for angiogenesis inducers and inhibitors began in 1971.…”

Hypoxia-induced downregulation of autophagy mediator Beclin-1 reduces the susceptibility of malignant intestinal epithelial cells to hypoxia-dependent apoptosis

“…This is due to the fact that treatments aimed at the suppression of tumor angiogenesis are now well established to block tumor growth, at least in part, by triggering hypoxiamediated death of cancer cell. [8][9][10][11] Some of the anti-angiogenic drugs, such as Avastin (bevacizumab), an anti-vascular endothelial growth factor function-blocking antibody, are presently being UCC CUA UUU, Beclin 1 siRNA-2: GGA AAU CAC UCG UAU CUG GUU, FADD siRNA-1 CGC CAA CGU UGA CAA GGU AUU, FADDsiRNA-2: GCU GAC CAG UGG AAC GUU AUU, casp-9siRNA-1 CGA GAG ACA UGC AGA UAU GUU, casp-9siRNA-2: GCG ACA UGA UCG AGG AUA UUU. All siRNAs were from Dharmacon.…”

“…[8][9][10][11] Anti-angiogenic therapy now represents one of the most promising approaches for cancer treatment. 12 Molecular mechanisms that regulate hypoxia-induced apoptosis of normal and cancer cells have recently begun to emerge but the understanding of these mechanisms is far from complete.…”