Modulation of the antitumor activity of metronomic cyclophosphamide by the angiogenesis inhibitor axitinib
Modulation of the antitumor activity of metronomic cyclophosphamide by the angiogenesis inhibitor axitinib
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DOI：
10.1158/1535-7163.mct-07-0584
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发表时间：
2008-01-01
影响因子：
5.7
通讯作者：
Waxman, David J.
中科院分区：
文献类型：
--
作者：
Ma, Jie;Waxman, David J.
血管生成抑制剂作为癌症治疗的单一疗法的有希望但仍然有限的功效表明需要将这些药剂整合到现有的治疗方案中。目前，我们研究了小分子血管生成抑制剂阿西替尼（AG-013736）的抗肿瘤活性及其与节拍环磷酰胺联合使用的潜力。阿昔替尼显著抑制大鼠9 L肿瘤s.c.但仅中度延迟肿瘤生长。阿昔替尼与节拍环磷酰胺的组合在药物治疗开始时完全阻断9 L肿瘤生长。相比之下，节拍环磷酰胺单独需要多个治疗周期来停止肿瘤生长。然而，与节拍环磷酰胺最终诱导的实质性肿瘤消退相反，阿西替尼/环磷酰胺组合是肿瘤生长静止的。阿昔替尼不抑制环磷酰胺的肝活化或其活化代谢物4-羟基-环磷酰胺（4-OH-CPA）向肝外组织的输出;相反，阿昔替尼选择性地使9 L肿瘤对4-OH-CPA的摄取降低30%至40%。4-OH-CPA的肿瘤渗透性降低与环磷酰胺诱导的肿瘤细胞凋亡减少和肿瘤相关宿主细胞中内源性血管生成抑制剂血小板反应蛋白-1的诱导阻断相关，这可能导致阿西替尼/环磷酰胺联合治疗不存在肿瘤消退。最后，阿西替尼瞬时增加9 L肿瘤细胞凋亡，表明其作用不限于内皮细胞群。这些研究结果突出了抗血管生成剂/节拍化疗组合的多种效应，并表明需要仔细优化药物治疗方案和剂量，以最大限度地提高抗肿瘤反应。
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 of the small-molecule angiogenesis inhibitor axitinib (AG-013736) and its potential for combination with metronomic cyclophosphamide. Axitinib significantly inhibited angiogenesis in rat 9L tumors grown s.c. in scid mice but only moderately delayed tumor growth. Combination of axitinib with metronomic cyclophosphamide fully blocked 9L tumor growth on initiation of drug treatment. In contrast, metronomic cyclophosphamide alone required multiple treatment cycles to halt tumor growth. However, in contrast to the substantial tumor regression that is ultimately induced by metronomic cyclophosphamide, the axitinib/cyclophosphamide combination was tumor growth static. Axitinib did not inhibit hepatic activation of cyclophosphamide or export of its activated metabolite, 4-hydroxy-cyclophosphamide (4-OH-CPA), to extrahepatic tissues; rather, axitinib selectively decreased 9L tumor uptake of 4-OH-CPA by 30% to 40%. The reduced tumor penetration of 4-OH-CPA was associated with a decrease in cyclophosphamide-induced tumor cell apoptosis and a block in the induction of the endogenous angiogenesis inhibitor thrombospondin-1 in tumor-associated host cells, which may contribute to the absence of tumor regression with the axitinib/cyclophosphamide combination. Finally, axitinib transiently increased 9L tumor cell apoptosis, indicating that its effects are not limited to the endothelial cell population. These findings highlight the multiple effects that may characterize antiangiogenic agent/metronomic chemotherapy combinations and suggest that careful optimization of drug scheduling and dosages will be required to maximize antitumor responses.