Dent Paul, Poklepovic Andrew, Booth Laurence, Hancock John F
Department of Biochemistry and Molecular Biology1, Virginia Commonwealth University, Richmond, VA 23298-0035, USA.
Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298-0035, USA.
Cancer Drug Resist. 2019 Dec 19;2(4):1032-1043. doi: 10.20517/cdr.2019.80. eCollection 2019.
The majority of scientists working in the field of cancer experimental therapeutics recognize that many drugs that claim to be "specific" for one target enzyme in fact regulate to varying degrees the activities of other additional protein targets. Some of these targets are known and are recognized as being an essential component of a drug's biology. However, many other targets fall into the category of "unknown unknowns". Thus, the collective therapeutic outcome for almost all clinically relevant drugs is reliant on both the claimed primary and secondary "on" targets as well as some of the unexpected unknown "off" targets. This review discusses the biology of several FDA approved cancer therapeutic drugs whose initial reported targets only represented the tip-of-the-iceberg in terms of how each agent acted as an anti-tumor drug. The review also discusses a putative thorough pre-visualization methodology for drug-based research, prior to executing any wet work. These approaches should be performed in an agnostic fashion and be based in part on the clinically safe drug's C max and its area under the curve in a patient. Based on tumor heterogeneity, considerations of how to approach developmental therapeutics in the age of "personalized medicine" are also discussed.
从事癌症实验治疗领域的大多数科学家都认识到，许多声称对一种靶酶具有“特异性”的药物实际上在不同程度上调节着其他额外蛋白质靶标的活性。其中一些靶标是已知的，并且被认为是药物生物学的重要组成部分。然而，许多其他靶标属于“未知的未知”类别。因此，几乎所有临床相关药物的总体治疗效果都依赖于声称的主要和次要“开启”靶标以及一些意想不到的未知“关闭”靶标。本综述讨论了几种美国食品药品监督管理局（FDA）批准的癌症治疗药物的生物学特性，这些药物最初报道的靶标在每种药物作为抗肿瘤药物的作用方式方面仅仅是冰山一角。该综述还讨论了在进行任何实验工作之前，一种用于基于药物研究的假定全面的预可视化方法。这些方法应以无偏见的方式进行，部分基于临床安全药物在患者体内的最大血药浓度（C max）及其曲线下面积。基于肿瘤异质性，还讨论了在“个性化医疗”时代如何开展开发性治疗的相关考虑因素。
