Ali-Osman F, Giblin J, Dougherty D, Rosenblum M L
Cancer Res. 1987 Jul 15;47(14):3718-24.
The biological half-lives and decay rate constants under the conditions of a human brain tumor clonogenic cell assay were determined for six clinically used anticancer agents. The agents studied were: 1,3-bis(2-chloroethyl)-1-nitrosourea; 3-(2-chloroethyl-3-nitrosoureido-2-deoxy-D-glucopyranose; cis-diaminedichloroplatinum(II); 2,5-diaziridinyl-3,6-bis-(carboethoxyamino)-1,4-benzoquinone; 4-demethylepipodophylotoxin-D-thylidene glucoside; and 9-hydroxy-2-N-methylellipticine. In vitro decay of all six drugs was found to be according to first order kinetics. The half-lives of two drugs, namely, 1,3-bis(2-chloroethyl-1-nitrosourea and 3-(2-chloroethyl-3-nitrosoureido-2-deoxy-D-glucopyranose under the human tumor clonogenic cell assay (HTCA) conditions were found to be similar to their terminal in vivo half-lives in humans. For the other drugs, however, there was a very large difference between their in vitro and in vivo pharmacokinetics. In the case of 2,5-diaziridinyl-3,6-bis(carboethoxyamine)-1,4-benzoquinone, we observed about an 80-fold difference between its in vitro half-life of 40.76 h and its in vivo terminal half-life of 0.52 h. We describe the principles upon which these data can be used to design clinically more relevant in vitro drug exposure protocols in HTCAs. Since, generally, tumor cells are exposed to drugs in the HTCA either continuously or for a specified duration, e.g., 1 or 2 h, we computed the initial in vitro drug concentrations to which tumor cells should be exposed such that the resulting in vitro (c X t) after a 2-h or a continuous exposure will be within clinically achievable levels. The application of these in vivo and in vitro pharmacokinetic principles will provide for more physiological testing of patient tumor cell sensitivity to anticancer drugs in the HTCA, and is likely to result in lower rates of false positive responses in clinical trials using clonogenic cell assays.
在人脑肿瘤克隆形成细胞试验条件下，测定了六种临床常用抗癌药物的生物半衰期和衰变率常数。所研究的药物有：1,3-双（2-氯乙基）-1-亚硝基脲；3-（2-氯乙基-3-亚硝基脲基）-2-脱氧-D-吡喃葡萄糖；顺二氨二氯铂（II）；2,5-二氮丙啶基-3,6-双（乙氧羰基氨基）-1,4-苯醌；4-去甲基表鬼臼毒素-D-亚乙基葡萄糖苷；以及9-羟基-2-N-甲基椭圆玫瑰树碱。发现所有六种药物的体外衰变均符合一级动力学。在人肿瘤克隆形成细胞试验（HTCA）条件下，发现1,3-双（2-氯乙基-1-亚硝基脲和3-（2-氯乙基-3-亚硝基脲基）-2-脱氧-D-吡喃葡萄糖这两种药物的半衰期与其在人体中的体内终末半衰期相似。然而，对于其他药物，它们的体外和体内药代动力学存在很大差异。就2,5-二氮丙啶基-3,6-双（乙氧羰基氨基）-1,4-苯醌而言，我们观察到其体外半衰期为40.76小时，而体内终末半衰期为0.52小时，两者相差约80倍。我们描述了可利用这些数据在HTCA中设计临床上更相关的体外药物暴露方案的原理。由于一般来说，肿瘤细胞在HTCA中要么持续暴露于药物，要么暴露特定时长，例如1或2小时，我们计算了肿瘤细胞应暴露的初始体外药物浓度，以使2小时或持续暴露后的体外（c×t）处于临床可达到的水平。这些体内和体外药代动力学原理的应用将为在HTCA中更生理地测试患者肿瘤细胞对抗癌药物的敏感性提供依据，并且可能会降低使用克隆形成细胞试验的临床试验中假阳性反应的发生率。
