Acton E M
Drugs Exp Clin Res. 1985;11(1):1-8.
Several simple test methods that revealed alterations in mechanisms of action proved to be useful in the selection of three new anthracycline analogues that are currently in preclinical development. 5-Iminodaunorubicin is a quinone-modified analogue, and the resultant suppression of quinone redox cycling appears to correlate with diminished cardiotoxicity rather than with any effect on antitumour activity. N,N-Dibenzyldaunorubicin is an inactive prodrug requiring metabolic activation, a process that appears to give some selectivity of action leading to improved activity. The cyanomorpholino derivative of doxorubicin shows an intense potency against tumours that is not encountered in other closely-related analogues, indicating a highly specific mode of action as yet unidentified. Results with these examples suggest that simple tests related to mechanisms of action may be more useful for analogue selection than extended tests to define antitumour activity.
几种揭示作用机制改变的简单测试方法，被证明在筛选三种目前正处于临床前开发阶段的新型蒽环类类似物时很有用。5-亚氨基柔红霉素是一种醌修饰的类似物，由此产生的醌氧化还原循环抑制似乎与心脏毒性降低相关，而不是与对抗肿瘤活性的任何影响相关。N，N-二苄基柔红霉素是一种需要代谢激活的无活性前药，这一过程似乎产生了一些作用选择性，从而提高了活性。阿霉素的氰基吗啉代衍生物对肿瘤显示出很强的效力，这在其他密切相关的类似物中并未出现，表明其作用模式高度特异，尚未明确。这些例子的结果表明，与作用机制相关的简单测试在类似物筛选中可能比用于定义抗肿瘤活性的扩展测试更有用。
