Low-dose metronomic combined with intermittent bolus-dose cyclophosphamide is an effective long-term chemotherapy treatment strategy

被引:102
作者
Shaked, Y
Emmenegger, U
Francia, G
Chen, L
Lee, CR
Man, S
Paraghamian, A
Ben-David, Y
Kerbel, RS
机构
[1] Sunnybrook & Womens Coll, Hlth Sci Ctr, Dept Mol & Cell Biol, Toronto, ON M4N 3M5, Canada
[2] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada
关键词
D O I
10.1158/0008-5472.CAN-05-0765
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Metronomic chemotherapy refers to the close, regular administration of comparatively low doses of cytotoxic drugs, with minimal or no drug-free breaks, over prolonged periods. It is thought to have an antiangiogenic basis. However, whereas surprisingly durable and potent tumor responses have been observed in a number of preclinical tumor models, relapses usually eventually occur using this type of treatment strategy. We therefore decided to test modified metronomic chemotherapy regimens that might significantly delay such relapses, but still maintain modest and acceptable toxicity profiles. Here, we show that repeated administration of bolus doses (BDs) of cyclophosphamide every 3 or 6 weeks, combined with a daffy oral low-dose metronomic (LDM) regimen (20 mg/kg/d cyclophosphamide), improves efficacy and significantly delays progression of transplanted PC-3 human prostate cancer xenografts, syngeneic transplanted EMT-6 breast tumors, and "spontaneous" murine erythroleukemia. Efficacy was superior whereas toxicity was mild and comparable to the LDM regimen, the latter assessed by body weight, neutrophil, lymphocyte, and total white blood counts. Antiangiogenic activity, measured by reduction in circulating endothelial precursor cells, revealed that the greatest degree of suppression occurred using the combination treatment. Overall, our results indicate that the administration of intermittent BD combined with chronic oral LDM cyclophosphamide is a potent treatment regimen for controlling tumor growth, which has a low toxicity profile, over prolonged periods of time.
引用
收藏
页码:7045 / 7051
页数:7
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