Metronomic Cyclophosphamide Enhances Response of Murine Subcutaneous Melanoma to Radiation

節拍器式Cyclophosphamide化學治療加強老鼠皮下黑色素瘤對放射線之反應

藍耿立(Keng-Li Lan) ； 施豪嶺(How-Ling Shih) ； 顏上惠(Sang-Hue Yen)

《放射治療與腫瘤學》 15卷3期 (2008/09) Pp. 213-221

https://doi.org/10.6316/TRO/200815(3)213

摘要

目的：近期研究顯示低劑量節拍器式施與化學藥物(metronomic chemotherapy)具有抑制血管新生之功效且不具顯著毒性。低劑量節拍器式施與cyclophosphamide在動物及人體實驗中顯現抑制腫瘤生長。數項研究顯示放射治療合併抑制血管新生可能具有加成或相加之療效，我們因此測試低劑量節拍器式施與cyclophosphamide及放射治療對老鼠皮下黑色素瘤之療效。
材料與方法：老鼠接受皮下黑色素瘤注射隔日在飲水中給予cyclophosphamide(0, 6, or 20 mg/kg/day)直到實驗結束。腫瘤注射第16天時，老鼠接受單一8Gy放射線照射，每週量測腫瘤的大小2次。
結果：低劑量節拍器式施與cyclophosphamide，可造成顯著的腫瘤生長抑制效果，而治療引起之毒性則不明顯。單一次數之8Gy放射治療抑制腫瘤生長而同時施與低劑量節拍器式cyclophosphamide則效果更形顯著，而推算之放射線強化係數(enhancementfactor)為2.4。
結論：低劑量節拍器式施與cyclophosphamide的臨床效益值得進一步探討，其與放射線治療之合併療效，與合併使用之適當劑量及順序之分子機制也值得在未來的研究中釐清。

關鍵字

低劑量節拍器式化療 ； 血管新生 ； 強化係數

並列摘要

Purpose: Encouraging results shown in recent literatures have demonstrated that low dose metronomic (LDM) chemotherapy exhibits antiangiogenic property with relatively safe profile. LDM cyclophosphamide has been studied in numerous pre-clinical studies and administrated to cancer patients with some beneficial effect on tumor stabilization. Given that several lines of evidence suggesting a potential synergistic or additive effect of antiangiogenic therapy and radiation, we examined whether the addition of LDM chemotherapy of cyclophosphamide could enhance the response of subcutaneously inoculated melanoma, B16F10, to radiation in a syngenic murine model.
Materials and Methods: One day after subcutaneous B16F10 inoculation on the flanks, c57/BL6 mice were given cyclophosphamide at 0, 6, or 20 mg/kg/day through drinking water on a daily basis throughout the whole course of experiment. On 16th day after tumor inoculation, tumors bearing mice, which were given 0 or 6 mg/kg/day were either irradiated with 8 Gy or left untreated. The tumor growths were measured two times per week for evaluation of the effects of various doses of LDM cyclophosphamide alone, radiation alone, or combination of both.
Results: LDM cyclophosphamide treatment significantly suppressed subcutaneous melanoma growth in a syngenic tumor model without discernible toxicity. Efficacy of LDM cyclophosphamide was demonstrated in a dose-dependent manner. A single fraction of 8 Gy radiation significantly delayed the growth of melanoma and the effect was further enhanced by concomitant administration of LDM cyclophosphamide with an enhancement factor of 2.4.
Conclusion: The clinical benefit of LDM cyclophosphamide may be further tested in clinical trials. It is also of great interests to further evaluate molecular mechanism of radiation and LDM cyclophosphamide combination regarding the dosing schedule and sequence.

並列關鍵字

Metronomic chemotherapy ； Angiogenesis ； Enhancement factor