Ma Jie, Waxman David J
Division of Cell and Molecular Biology, Department of Biology, Boston University, 5 Cummington Street, Boston, MA 02215, USA.
Mol Cancer Ther. 2008 Jan;7(1):79-89. doi: 10.1158/1535-7163.MCT-07-0584.
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.
血管生成抑制剂作为癌症单药治疗虽前景广阔但疗效仍有限，这表明有必要将这些药物纳入现有的治疗方案中。目前，我们研究了小分子血管生成抑制剂阿昔替尼（AG - 013736）的抗肿瘤活性及其与节拍性环磷酰胺联合使用的潜力。阿昔替尼显著抑制了在scid小鼠皮下生长的大鼠9L肿瘤中的血管生成，但仅适度延迟了肿瘤生长。阿昔替尼与节拍性环磷酰胺联合使用在开始药物治疗时完全阻断了9L肿瘤的生长。相比之下，单独使用节拍性环磷酰胺需要多个治疗周期才能阻止肿瘤生长。然而，与节拍性环磷酰胺最终诱导的显著肿瘤消退不同，阿昔替尼/环磷酰胺联合治疗使肿瘤生长停滞。阿昔替尼不抑制环磷酰胺的肝脏激活或其活性代谢产物4 - 羟基环磷酰胺（4 - OH - CPA）向肝外组织的转运；相反，阿昔替尼选择性地使9L肿瘤对4 - OH - CPA的摄取降低了30%至40%。4 - OH - CPA在肿瘤中的渗透减少与环磷酰胺诱导肿瘤细胞凋亡的减少以及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诱导的阻断有关，这可能导致阿昔替尼/环磷酰胺联合治疗缺乏肿瘤消退。最后，阿昔替尼短暂增加了9L肿瘤细胞凋亡，表明其作用不限于内皮细胞群体。这些发现突出了抗血管生成药物/节拍性化疗联合治疗可能具有的多种效应，并表明需要仔细优化药物给药方案和剂量以最大化抗肿瘤反应。
