Blagosklonny Mikhail V
Ordway Research Institute and Oncotarget Inc., Albany, NY, USA.
Cell Cycle. 2008 May 15;7(10):1307-12. doi: 10.4161/cc.7.10.6250. Epub 2008 May 8.
The Gotham Prize was awarded to Alex Varshavsky for "Targeting the absence", a strategy employing negative targets of cancer therapy. This is a brilliant example of therapeutic engineering: designing a sequence of events that leads to the selective killing of one type of cell, while sparing all others. A complex molecular device (Varshavsky's Demon) examines DNA, recognizes the present target in normal cells and kills cancer cells. The strategy is limited by the delivery (transfection or infection) of DNA-based devices into each cell of our body. How can we overcome this limitation? Can therapeutic engineering be applied to small drugs? Can each small molecule reach a cell separately and, once in a cell, exert orchestrated action governed by cellular context? Here I describe how a combination of small drugs can acquire a demonic power to check, choose and selectively kill. The cytotoxicity is restricted to cells lacking (or having) one of the targets. For example, in the presence of a normal target, one drug can cancel the cytotoxic action of another drug. And by increasing a number of targets, we can increase the precision and power of such 'restrictive' combinations. Here I discuss restrictive combinations of currently available drugs that could be tested in clinical trials. Could then these combinations cure cancer today? And what does 'cure' really mean? This article suggests the answer.
哥谭奖授予了亚历克斯·瓦尔沙夫斯基，以表彰他的“靶向缺失”策略，这是一种采用癌症治疗阴性靶点的策略。这是治疗工程的一个杰出范例：设计一系列事件，导致选择性杀死一种类型的细胞，同时使其他所有细胞得以存活。一种复杂的分子装置（瓦尔沙夫斯基的“恶魔”）会检查DNA，识别正常细胞中的现有靶点并杀死癌细胞。该策略受到将基于DNA的装置递送至我们身体每个细胞（转染或感染）的限制。我们如何克服这一限制？治疗工程能否应用于小分子药物？每个小分子能否分别进入一个细胞，并且一旦进入细胞，就能根据细胞环境发挥协调作用？在此，我将描述小分子药物的组合如何能够获得一种魔力，进行检查、选择并选择性地杀死细胞。细胞毒性仅限于缺乏（或具有）其中一个靶点的细胞。例如，在存在正常靶点的情况下，一种药物可以抵消另一种药物的细胞毒性作用。通过增加靶点数量，我们可以提高这种“限制性”组合的精准度和效力。在此，我将讨论目前可用药物的限制性组合，这些组合可在临床试验中进行测试。那么这些组合如今能治愈癌症吗？“治愈”到底意味着什么？本文给出了答案。
