Jackson R C
Agouron Pharmaceuticals, Inc., San Diego, CA 92121.
J Natl Cancer Inst. 1993 Apr 7;85(7):539-45. doi: 10.1093/jnci/85.7.539.
Maintaining homeostasis is the biological function of negative feedback, a process that plays a well-understood role in the biochemistry of antimetabolite drugs. An equally important property of living systems--the ability to respond to external stimuli by switching rapidly from one state to another--is mediated by positive feedback. Kinetic analysis of multi-enzyme biochemical pathways has shown that pathways containing positive feedback coupled with negative feedback may act as biochemical switching systems in which multiple steady states are possible.
A computer model was used to study the kinetic effects of antimetabolites that inhibit biochemical pathways at positive feedback sites and to determine whether the kinetics of such systems differed from those of classical antimetabolites.
Kinetics were simulated by microcomputer to model the effects of inhibitors on a simplified metabolic pathway.
Antimetabolite drugs that act at positive feedback sites are predicted to display highly nonclassical properties. Three nonclassical properties are kinetically possible. First, the drugs may switch off the pathway at substoichiometric concentrations; classical antimetabolites require stoichiometric levels and sometimes much more. Second, instead of demonstrating classical continuous inhibition, antimetabolite drugs that act at positive feedback sites may give "all-or-none" dose-response curves with discontinuity at a specific value. Inhibitor concentrations below this value would have no overall effect on the system, while inhibitor concentrations at or above this value would give an abrupt transition to an inhibited steady state. Third, the inhibited system may show hysteresis and remain switched off after the inhibitor is removed.
These findings suggest that antimetabolites acting at switch points could have kinetic properties very different from those of classical antimetabolites and could provide a noncytotoxic method of switching off pathways in neoplastic cells, perhaps leading to cell stasis.
Experimental validation of these conclusions will require identification of the positive feedback sites of metabolic and signaling pathways and exploration of the effects of inhibitors of these sites. The properties of "switch antimetabolites" should prompt a search for new kinds of targets for drug design.
维持体内平衡是负反馈的生物学功能，这一过程在抗代谢药物的生物化学中发挥着为人熟知的作用。生命系统的一个同样重要的特性——通过迅速从一种状态转换到另一种状态来响应外部刺激的能力——是由正反馈介导的。对多酶生化途径的动力学分析表明，包含正反馈与负反馈相结合的途径可能充当生化开关系统，其中可能存在多个稳态。
使用计算机模型研究在正反馈位点抑制生化途径的抗代谢物的动力学效应，并确定此类系统的动力学是否不同于经典抗代谢物的动力学。
通过微型计算机模拟动力学，以模拟抑制剂对简化代谢途径的影响。
预计作用于正反馈位点的抗代谢药物会表现出高度非经典的特性。在动力学上有三种非经典特性是可能的。首先，这些药物可能在亚化学计量浓度下关闭途径；经典抗代谢物需要化学计量水平，有时还需要更多。其次，作用于正反馈位点的抗代谢药物不是表现出经典的持续抑制，而是可能给出“全或无”的剂量反应曲线，在特定值处有间断。低于该值的抑制剂浓度对系统没有总体影响，而等于或高于该值的抑制剂浓度会导致突然转变为抑制稳态。第三，受抑制的系统可能表现出滞后现象，并且在去除抑制剂后仍保持关闭状态。
这些发现表明，作用于开关点的抗代谢物可能具有与经典抗代谢物非常不同的动力学特性，并可能提供一种关闭肿瘤细胞中途径的非细胞毒性方法，或许会导致细胞停滞。
对这些结论的实验验证将需要鉴定代谢和信号通路的正反馈位点，并探索这些位点抑制剂的作用。“开关抗代谢物”的特性应促使人们寻找新型药物设计靶点。
