Wadler S, Green M D, Basch R, Muggia F M
Biochem Pharmacol. 1987 May 1;36(9):1495-501. doi: 10.1016/0006-2952(87)90116-x.
Doxorubicin and the bisdioxopiperazine, ICRF 187, synergistically inhibit proliferation of murine sarcoma S180 cells in vitro. Cell cycle analysis was employed to help discriminate cytokinetic from lethal effects of the drug combination. Twenty-four-hour incubation with either agent produced dose-dependent partial G2M arrest. At high doses, ICRF 187 produced partial G2M arrest, inhibition of cell division, and continued DNA synthesis at a higher ploidy, resulting in a second G2M arrest of an 8n population. The addition of ICRF 187 to doxorubicin resulted in enhancement of cell cycle blockade at G2M. The combination also produced enhanced lethality as measured by reduced colony-forming efficiency of drug-treated S180 cells. Measurement of [14C]doxorubicin accumulation in, and effux from, ICRF 187 pretreated cells failed to reveal an effect of pretreatment with the bisdioxopiperazine on anthracycline disposition by S180 cells, suggesting that the enhanced cytotoxic and cytostatic effects do not result from increased intracellular concentrations of doxorubicin. The positive interaction between the two drugs may represent site-specific enhancement of the anthracycline effect by ICRF 187 at an intracellular target site.
阿霉素与双二氧哌嗪ICRF 187在体外协同抑制小鼠肉瘤S180细胞的增殖。采用细胞周期分析来帮助区分药物组合的细胞动力学效应和致死效应。单独使用这两种药物中的任何一种进行24小时孵育都会产生剂量依赖性的部分G2M期阻滞。高剂量时，ICRF 187会导致部分G2M期阻滞、细胞分裂抑制，并在更高倍体水平上持续进行DNA合成，从而导致8倍体群体出现第二次G2M期阻滞。将ICRF 187添加到阿霉素中会增强G2M期的细胞周期阻滞。通过检测经药物处理的S180细胞集落形成效率降低，发现该组合还产生了增强的致死性。对经ICRF 187预处理的细胞中[14C]阿霉素的摄取和流出进行测量，未发现双二氧哌嗪预处理对S180细胞蒽环类药物处置有影响，这表明增强的细胞毒性和细胞抑制作用并非由阿霉素细胞内浓度增加所致。两种药物之间的正向相互作用可能代表ICRF 187在细胞内靶位点对蒽环类药物作用的位点特异性增强。
