Myelotoxic effects of the bifunctional alkylating agent bizelesin on human, canine and murine myeloid progenitor cells
Myelotoxic effects of the bifunctional alkylating agent bizelesin on human, canine and murine myeloid progenitor cells
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DOI：
10.1007/s002800050550
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发表时间：
1996-11-01
影响因子：
3
通讯作者：
Grieshaber, CK
中科院分区：
文献类型：
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作者：
Volpe, DA;Tomaszewski, JE;Grieshaber, CK
Bizelesin是抗癌剂CC-1065的有效合成衍生物，优先烷基化并结合DNA的小格罗夫。临床前动物研究发现，比泽来新对比格犬的毒性大于对啮齿动物的毒性，骨髓抑制是剂量限制性毒性。这种毒性在所有种属中均具有剂量和时间依赖性。由于种属间体内骨髓毒性存在显著差异，因此在药效学基础上确定哪一种最接近人类非常重要。因此，利用造血克隆测定来评价比折来新对粒细胞-巨噬细胞（CFU-gm）集落形成的影响。将骨髓细胞在体外暴露于bizelesin（0.001-1000 nM）1或8小时，然后测定集落形成。鼠CFU-gm与人或犬CFU-gm发生100%集落抑制时（1或8 h）的药物浓度存在3-log差异。比泽来新暴露8小时后，人CFU-gm的IC 70值（0.006 +/- 0.002 nM）比鼠CFU-gm的IC 70值（13.32 +/- 8.31 nM）低2220倍。在任何给定浓度下，对于所有物种，8小时药物暴露导致比1小时暴露更大的集落抑制（P < 0.05）。增加暴露时间从1至8小时增加的毒性，人类和犬CFU-GM远远超过鼠CFU-GM。临床配制的药物溶液是比溶解在DMSO中的药物更有效的人集落形成抑制剂。暴露1小时后，配制的比泽来新（0.106 +/- 0.105 nM）对人CFU-gm的IC 70值比DMSO中的原料药（0.184 +/- 0.044 nM）低1.7倍。这些体外克隆试验的结果与整体动物研究中观察到的结果定性一致，表明bizelesin将成为临床上有效的骨髓抑制剂。由于临床前模型中的剂量限制性毒性是骨髓抑制，并且人和犬CFU-gm的体外敏感性相似，因此犬最大耐受剂量（MTD）优于鼠MTD，以确定I期临床试验的安全起始剂量。
Bizelesin is a potent synthetic derivative of the anticancer agent CC-1065 that preferentially alkylates and binds the minor grove of DNA. Preclinical animal studies have found bizelesin to be more toxic to beagle dogs than to rodents and that myelosuppression was the dose-limiting toxicity. This toxicity was dose- and time-dependent in all species. Due to the significant difference in the in vivo myelotoxicity between species, it was important to determine which one most closely resembles humans on a pharmacodynamic basis. Therefore, hematopoietic clonal assays were utilized to evaluate the effects of bizelesin on granulocyte-macrophage (CFU-gm) colony formation. Marrow cells were exposed in vitro to bizelesin (0.001-1000 nM) for 1 or sh and then assayed for colony formation. There was a 3-log difference in drug concentration at which 100% colony inhibition occurred (1 or 8 h) for murine CFU-gm versus human or canine CFU-gm. The IC70 value after an 8-h bizelesin exposure for human CFU-gm (0.006 +/- 0.002 nM) was 2220-times lower than for murine CFU-gm (13.32 +/- 8.31 nM). At any given concentration, an 8 h drug exposure resulted in greater colony inhibition than a 1 h exposure for all species (P < 0.05). Increasing exposure time from 1 to 8 h increased toxicity to human and canine CFU-gm much more than to murine CFU-gm. The clinically formulated drug solution was a more potent inhibitor of human colony formation than drug dissolved in DMSO. The IC70 value after a 1-h exposure was 1.7 times lower for human CFU-gm with formulated bizelesin (0.106 +/- 0.105 nM) than bulk drug in DMSO (0.184 +/- 0.044 nM). The results of these in vitro clonal assays were qualitatively consistent with those seen in whole animal studies, suggesting that bizelesin will be a potent myelosuppressive agent in the clinic. Since the dose-limiting toxicity in preclinical models is myelosuppression and the in vitro sensitivity of human and canine CFU-gm is similar, the canine maximum tolerated dose (MTD) is better than the murine MTD to determine a safe starting dose for phase I clinical trials.