Drewinko B, Barlogie B
Cancer Treat Rep. 1976 Sep;60(9):1295-1306.
The lethal and kinetic effects of VP-16-213 were analyzed in a human lymphoid cell line (T1 cells) in vitro. When asynchronous T1 cells were exposed to increasing concentrations of VP-16-213 for 1 hour, an exponential survival curve with a Do (mean lethal dose equal to the concentration required to reduce survival by 63% on the exponential part of the survival curve) of 3 mug/ml was obtained. Increasing exposure time also reduced survival exponentially. Synchronized cells showed age-dependent sensitivity to VP-16-213 with the greatest lethal damage experienced by cells treated in S and G2 phase. The major kinetic response of the T1 cells to VP-16-213 was a delay in G2 phase, the extent and duration of which was a function of drug concentration, exposure time, and cell cycle stage of drug addition; thus, cells in S phase were most effectively blocked in the subsequent G2 phase. Continuous treatment with concentrations of VP-16-213 (greater than 0.5 mug/ml for greater than 3 hours) caused a retardation of S-phase transit with prompt recovery after drug release. Treatment with 10.0 mug/ml for greater than 3 hours resulted in a "frozen state" of the whole life cycle, inducing only minor compartment changes. DNA synthesis was inhibited in the majority of cells with an S-phase DNA content. There was no correlation between the extent of perturbation and lethal effects after treatment with VP-16-213.
在体外对人淋巴细胞系（T1细胞）分析了依托泊苷（VP - 16 - 213）的致死和动力学效应。当将异步T1细胞暴露于浓度递增的VP - 16 - 213中1小时，得到一条指数存活曲线，其Do（平均致死剂量，等于在存活曲线指数部分使存活率降低63%所需的浓度）为3微克/毫升。延长暴露时间也会使存活率呈指数下降。同步化细胞对VP - 16 - 213表现出年龄依赖性敏感性，处于S期和G2期处理的细胞受到的致死损伤最大。T1细胞对VP - 16 - 213的主要动力学反应是G2期延迟，其程度和持续时间是药物浓度、暴露时间以及添加药物时细胞周期阶段的函数；因此，处于S期的细胞在随后的G2期被最有效地阻断。用浓度大于0.5微克/毫升的VP - 16 - 213持续处理超过3小时会导致S期进程延迟，药物去除后迅速恢复。用10.0微克/毫升处理超过3小时会导致整个生命周期处于“冻结状态”，仅诱导轻微的区室变化。大多数具有S期DNA含量的细胞中DNA合成受到抑制。用VP - 16 - 213处理后，扰动程度与致死效应之间没有相关性。
