Walton M I, Goddard P, Kelland L R, Thurston D E, Harrap K R
CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Belmont, Surrey, UK.
Cancer Chemother Pharmacol. 1996;38(5):431-8. doi: 10.1007/s002800050507.
We examined the in vitro cytotoxicity, antitumour activity and preclinical pharmacokinetics of the novel sequence-selective, bifunctional alkylating agent DSB-120, a synthetic pyrrolo[1,4][2,1-c]benzodiazepine dimer. DSB-120 was shown to be a potent cytotoxic agent in vitro against a panel of human colon carcinomas [50% growth-inhibitory concentration (IC50) 42 +/- 7.9 nM, mean +/- SE, n = 7] and two rodent tumours (L1210 and ADJ/PC6). Antitumour activity was assessed in the bifunctional alkylating-agent-sensitive murine plasmacytoma ADJ/PC6 using a variety of administration protocols. The maximal antitumour effects were observed following a single i.v. dose but the therapeutic index was only 2.6. DSB-120 was less effective when given i.p. either singly or by a daily x 5 schedule. After a single i.v. dose at the maximum tolerated dose (MTD, 5 mgkg-1) the plasma elimination was biphasic, with a short distribution phase (t1/2 alpha 4 min) being followed by a longer elimination phase (t1/2 beta 38 min). Peak plasma concentrations were 25 micrograms ml-1, the clearance was 1.3 ml g-1 h-1 and the AUC0-infinity was 230 micrograms ml-1 min. Concentrations of DSB-120 in ADJ/PC6 tumours were very low, showing a peak of 0.4 micrograms g-1 at 5 min. The steady-state tumour/plasma ratio was about 5% and the AUC was only 2.5% of that occurring in the plasma. DSB-120 appeared to be unstable in vivo, with only 1% of an administered dose being recovered unchanged in 24-h urine samples. Plasma protein binding was extensive at 96.6%. In conclusion, the poor antitumour activity of DSB-120 may be a consequence of low tumour selectivity and drug uptake as a result of high protein binding and/or extensive drug metabolism in vivo.
我们研究了新型序列选择性双功能烷化剂DSB - 120（一种合成的吡咯并[1,4][2,1 - c]苯并二氮杂卓二聚体）的体外细胞毒性、抗肿瘤活性和临床前药代动力学。结果表明，DSB - 120在体外对一组人结肠癌[50%生长抑制浓度（IC50）为42±7.9 nM，平均值±标准误，n = 7]以及两种啮齿动物肿瘤（L1210和ADJ/PC6）是一种有效的细胞毒性剂。使用多种给药方案在对双功能烷化剂敏感的小鼠浆细胞瘤ADJ/PC6中评估抗肿瘤活性。单次静脉注射后观察到最大抗肿瘤效果，但治疗指数仅为2.6。单独腹腔注射或以每日×5的方案给药时，DSB - 120的效果较差。在最大耐受剂量（MTD，5 mg kg⁻¹）下单次静脉注射后，血浆消除呈双相性，先是短的分布相（t1/2α 4分钟），随后是较长的消除相（t1/2β 38分钟）。血浆峰值浓度为25微克/毫升，清除率为1.3毫升/克/小时，AUC0 - ∞为230微克/毫升·分钟。DSB - 120在ADJ/PC6肿瘤中的浓度非常低，在5分钟时达到峰值0.4微克/克。稳态肿瘤/血浆比约为5%，AUC仅为血浆中AUC的2.5%。DSB - 120在体内似乎不稳定，在24小时尿液样本中仅回收了1%未改变的给药剂量。血浆蛋白结合率高达96.6%。总之，DSB - 120抗肿瘤活性差可能是由于肿瘤选择性低以及由于高蛋白结合和/或体内广泛的药物代谢导致药物摄取不足所致。
