Lowis S P, Newell D R, Pearson A D
Cancer Research Unit, University of Newcastle-upon-Tyne, U.K.
Eur J Cancer. 1995;31A(4):622-6. doi: 10.1016/0959-8049(95)00026-f.
Using an in vitro clonogenic assay system, we examined the relationship between concentration, duration and schedule of exposure to etoposide and cytotoxicity in three cell lines. Two cell lines (SK-N-SH and IMR32) were derived from human neuroblastomas, and one (L1210) was the original murine leukaemia cell line used to define schedule dependency of etoposide in vivo. Cytotoxicity was found to be determined by the product of concentration and duration of exposure over a 120-fold range of durations and a 100-fold range of concentrations. No difference in cytotoxicity was seen following equivalent exposure either continuously or in two separate intervals. In one cell line, exposure to etoposide when at confluence led to a highly resistant subpopulation comprising 10-15% of the entire cell number. This did not seem to be associated with any difference in the rate of etoposide efflux from cells preloaded with 3H-etoposide. We conclude that etoposide does not show schedule dependency in vitro, but cytotoxicity is related to total exposure to etoposide. The schedule dependency seen in vivo may possibly arise from host pharmacokinetic factors.
利用体外克隆形成试验系统，我们研究了依托泊苷的浓度、暴露持续时间和给药方案与三种细胞系细胞毒性之间的关系。两种细胞系（SK-N-SH和IMR32）源自人神经母细胞瘤，另一种（L1210）是最初用于确定依托泊苷体内给药方案依赖性的小鼠白血病细胞系。在120倍的持续时间范围和100倍的浓度范围内，发现细胞毒性由暴露浓度和持续时间的乘积决定。连续暴露或分两个间隔进行等效暴露后，细胞毒性没有差异。在一个细胞系中，汇合时暴露于依托泊苷会导致形成一个高度耐药的亚群，占整个细胞数的10%-15%。这似乎与预先加载3H-依托泊苷的细胞中依托泊苷流出速率的任何差异无关。我们得出结论，依托泊苷在体外不显示给药方案依赖性，但细胞毒性与依托泊苷的总暴露量有关。体内观察到的给药方案依赖性可能源于宿主药代动力学因素。
