Rockwell S, Grindey G B
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06510.
Oncol Res. 1992;4(4-5):151-5.
EMT6 mouse mammary tumor cells were used to examine the cytotoxic effects of 2',2'-difluorodeoxycytidine (gemcitabine; dFdC) alone and in combination with radiation. The cytotoxicity of dFdC differed from that of most antimetabolites. The concentration-response curve for exponentially growing cells treated for 4 hr with various drug concentrations was exponential down to a surviving fraction of 0.05; thus, dFdC appeared to kill cells in all phases of the cell cycle, rather than killing only the S-phase cells that compose approximately 50% of the cell population. High concentrations of dFdC were toxic to cells in plateau phase EMT6 cultures, as well as to cells in rapidly proliferating cultures. These findings are thought to reflect the unusual cellular pharmacokinetics of the compound. Treatment of exponentially growing cultures with dFdC before, during, and after irradiation was extremely effective in killing the cells; the survival curves for cells treated with drug plus radiation were statistically compatible with either additive cytotoxicity or a synergistic effect (i.e., radiosensitization by dFdC). These studies also provided evidence that dFdC released by dying cells could produce delayed cytotoxic effects on cells not treated directly with dFdC. These data provide several bases for expecting beneficial therapeutic effects from antineoplastic regimens combining dFdC plus radiation.
EMT6小鼠乳腺肿瘤细胞被用于检测2',2'-二氟脱氧胞苷（吉西他滨；dFdC）单独及与放疗联合使用时的细胞毒性作用。dFdC的细胞毒性与大多数抗代谢物不同。用不同药物浓度处理指数生长期细胞4小时，其浓度-反应曲线呈指数下降，直至存活分数降至0.05；因此，dFdC似乎能杀死细胞周期所有阶段的细胞，而不仅仅是杀死占细胞群体约50%的S期细胞。高浓度的dFdC对处于平台期的EMT6培养细胞以及快速增殖培养的细胞均有毒性。这些发现被认为反映了该化合物不同寻常的细胞药代动力学。在照射前、照射期间和照射后用dFdC处理指数生长期培养物，在杀死细胞方面极其有效；用药物加放疗处理的细胞的存活曲线在统计学上与相加细胞毒性或协同效应（即dFdC的放射增敏作用）相符。这些研究还提供了证据，表明死亡细胞释放的dFdC可对未直接用dFdC处理的细胞产生延迟的细胞毒性作用。这些数据为预期dFdC加放疗的抗肿瘤方案产生有益的治疗效果提供了几个依据。
