Modulation of the Antitumor Activity of Metronomic Cyclophosphamide by the Angiogenesis Inhibitor Axitinib

摘要: The promising but still limited efficacy of angiogenesis inhibitors as monotherapies for cancer treatment indicates a need to integrate these agents into existing therapeutic regimens. Presently, we investigate the antitumor activity small-molecule inhibitor axitinib (AG-013736) and its potential combination with metronomic cyclophosphamide. Axitinib significantly inhibited in rat 9L tumors grown s.c. scid mice only moderately delayed tumor growth. Combination cyclophosphamide fully blocked growth on initiation drug treatment. In contrast, alone required multiple cycles halt However, contrast substantial regression that is ultimately induced by cyclophosphamide, axitinib/cyclophosphamide was static. did not inhibit hepatic activation or export activated metabolite, 4-hydroxy-cyclophosphamide (4-OH-CPA), extrahepatic tissues; rather, selectively decreased uptake 4-OH-CPA 30% 40%. reduced penetration associated decrease cyclophosphamide-induced cell apoptosis block induction endogenous thrombospondin-1 tumor-associated host cells, which may contribute absence combination. Finally, transiently increased apoptosis, indicating effects are endothelial population. These findings highlight characterize antiangiogenic agent/metronomic chemotherapy combinations suggest careful optimization scheduling dosages will be maximize responses.