Adams D J, Watkins P J, Knick V C, Tuttle R L, Bair K W
Division of Cell Biology, Burroughs Wellcome, Research Triangle Park, North Carolina 27709.
Cancer Res. 1990 Jun 15;50(12):3663-9.
The pharmacodynamics of a new series of antitumor DNA intercalators, known as arylmethylaminopropanediols (AMAPs), has been evaluated in vitro against adherent (MCF-7 human breast cancer) and nonadherent (P388 murine leukemia) cell lines. Previous work had shown that the in vitro antitumor activity of the model AMAP crisnatol was a function of exposure (Cn x T), rather than concentration alone. A unique exposure parameter, the minimum C x T, was proposed as an end point for antitumor activity in cell culture. Comparison of crisnatol to several established agents by the minimum C x T versus the standard concentration producing 10% survival indicated that these end points were not equivalent. The current work examined the validity of the pharmacodynamic approach using AMAP isomers from three different ring systems that were known to exhibit a spectrum of activity against the P388 tumor in vivo. The results indicated that antiproliferative, but not cytotoxic, activity of AMAPs in the pharmacodynamic assay correlated with their differential activity in vivo, expressed as percentage of increase in life span. In contrast, the concentration producing 10% survival either at 1 h or after continuous exposure did not show a similar correlation. The pharmacodynamic assay also revealed that certain AMAPs, while equipotent by concentration alone, required significantly less time and therefore less overall exposure for efficacy. Finally, the activity of AMAP isomers in P388 cells differed from that in MCF-7 cells, which may indicate AMAP selectivity for certain tumor types. Since AMAP action was a function of exposure, drug effects on cellular targets could likewise depend on exposure rather than concentration. These findings emphasize the importance of relating drug mechanisms to the pharmacodynamics of anticancer agents.
一系列新型抗肿瘤DNA嵌入剂，即芳基甲基氨基丙二醇（AMAPs），已在体外针对贴壁（MCF - 7人乳腺癌）和非贴壁（P388小鼠白血病）细胞系进行了药效学评估。先前的研究表明，模型AMAP克立那托的体外抗肿瘤活性是暴露量（Cn×T）的函数，而非单纯浓度的函数。提出了一个独特的暴露参数——最小C×T，作为细胞培养中抗肿瘤活性的终点指标。通过将克立那托与几种已确立的药物按最小C×T与产生10%存活率的标准浓度进行比较，结果表明这些终点指标并不等效。当前的研究考察了使用来自三种不同环系的AMAP异构体的药效学方法的有效性，这些异构体已知在体内对P388肿瘤表现出一系列活性。结果表明，在药效学测定中，AMAPs的抗增殖活性（而非细胞毒性活性）与其在体内的差异活性相关，以寿命延长百分比表示。相比之下，在1小时或连续暴露后产生10%存活率的浓度并未显示出类似的相关性。药效学测定还表明，某些AMAPs虽然仅按浓度衡量效力相当，但达到药效所需的时间显著更短，因此总体暴露量更少。最后，AMAP异构体在P388细胞中的活性与在MCF - 7细胞中的活性不同，这可能表明AMAP对某些肿瘤类型具有选择性。由于AMAP的作用是暴露量的函数，药物对细胞靶点的作用同样可能取决于暴露量而非浓度。这些发现强调了将药物作用机制与抗癌药物药效学相关联的重要性。
