Bill C A, Garrett K C, Harrell R, Tofilon P J
Department of Experimental Radiotherapy, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Radiat Res. 1992 Mar;129(3):315-21.
Several agents that induce differentiation have previously been shown to induce the terminal differentiation of leukemic cells and enhance the radiosensitivity of certain solid tumor cell lines in vitro using millimolar concentrations. We now report that aclacinomycin A (ACM), a potent inducer of leukemic cell differentiation in vitro, can significantly enhance the radiosensitivity of a human colon tumor cell line (Clone A) at a concentration of 10 nM. Based on colony-forming efficiency, the maximum increase in radiosensitivity was found using 15 nM ACM for 3 days with a dose enhancement factor of 1.4 at a surviving fraction of 0.10. This treatment increased cell doubling time, but had no effect on cell-cycle phase distribution. To gain insight into the mechanisms responsible for this radiosensitization, gamma-ray-induced DNA single- and double-strand breaks were examined. Aclacinomycin A had no effect on the induction of DNA single-strand breaks but significantly enhanced the formation of gamma-ray-induced DNA double-strand breaks. The rate or extent of repair of the induced double-strand breaks was not influenced by ACM treatment. These data suggest that ACM, at achievable plasma concentrations, can enhance the radiosensitivity of a human tumor cell line by increasing the initial level of radiation-induced DNA double-strand breaks.
此前已表明，几种诱导分化的试剂在体外使用毫摩尔浓度时可诱导白血病细胞终末分化，并增强某些实体瘤细胞系的放射敏感性。我们现在报告，阿克拉霉素A（ACM），一种在体外有效诱导白血病细胞分化的试剂，在浓度为10 nM时可显著增强人结肠肿瘤细胞系（克隆A）的放射敏感性。基于集落形成效率，在存活分数为0.10时，使用15 nM ACM处理3天发现放射敏感性最大增加，剂量增强因子为1.4。这种处理增加了细胞倍增时间，但对细胞周期阶段分布没有影响。为了深入了解这种放射增敏作用的机制，研究了γ射线诱导的DNA单链和双链断裂。阿克拉霉素A对DNA单链断裂的诱导没有影响，但显著增强了γ射线诱导的DNA双链断裂的形成。诱导的双链断裂的修复速率或程度不受ACM处理的影响。这些数据表明，在可达到的血浆浓度下，ACM可通过增加辐射诱导的DNA双链断裂的初始水平来增强人肿瘤细胞系的放射敏感性。
