Topoisomerase Targeting Agents Predicated on Polyamine Architectures

描述(由申请人提供)：针对拓扑异构酶作用的药物是有效的抗癌药物，许多药物已获得FDA批准。抗拓扑异构酶治疗的基础是将内源性拓扑异构酶颠覆为一种遗传毒性的DNA损伤剂。这类药物的一个重要问题是对正常细胞的附带损害。由于所有有核的体细胞都保持一定水平的拓扑异构酶活性(I型和/或II型)，因此在正常的健康组织中，由于DNA损伤而导致的负面结果是不可避免的，除非能设计出新的策略来减少不良副作用。在本SBIR中，企业赞助商(TopOGEN，Inc.)正在提出一种使用“智能制药”药物设计的组合策略。强大的拓扑异构酶毒药可以与多胺(例如精胺)偶联，而多胺是癌细胞基于细胞生长对外源多胺的需求增加而优先处理的。有证据表明，新型抗拓扑异构酶/多胺结合物通过内源性拓扑异构酶中毒在具有高活性多胺转运机制的细胞中诱导优先DNA损伤。已经合成了一系列这种新的多胺化合物(还在不断地添加其他化合物)。在这项SBIR中，该公司将使用定义的模型细胞系在体内和使用纯化的酶在体外严格评估这些新化合物的拓扑异构酶靶向功效。这一合理的多胺-拓扑异构酶药物设计策略将揭示最有效的癌细胞杀伤剂，同时将对正常细胞的损害降至最低。与公共卫生相关：有针对性的癌症疗法的发展将是癌症治疗的一个明显进步。由于2005年美国癌症造成近140万人死亡和2100亿美元的损失，因此投资于新的制药技术在医疗和经济上都是有意义的。可以选择性地靶向并杀死癌症的智能药物将开始解决这一重要的公共卫生问题。

DESCRIPTION (provided by applicant): Drugs that target topoisomerase action are effective anticancer agents and a number are FDA approved. Anti-topoisomerase therapy is predicated on subverting the endogenous topoisomerase into a genotoxic, DNA damaging agent. A significant problem with such drugs is collateral damage in normal cells. Since all nucleated somatic cells retain some level topoisomerase activity (either type I and/or type II), negative outcome due to DNA damage in normal healthy tissue is unavoidable, unless novel strategies can be crafted to tune down undesirable side effects. In this SBIR, the corporate sponsor (TopoGEN, Inc.) is proposing a combinatorial strategy using `smart pharma' drug design. Potent topoisomerase poisons can be coupled to polyamines (spermine for example) which are processed preferentially by cancer cells based on elevated requirement of exogenous polyamines for cell growth. Evidence is provided that novel anti- topoisomerase/polyamine conjugates induce preferential DNA damage via endogenous topoisomerase poisoning in cells with hyperactive polyamine transport mechanisms. A library of novel polyamine compounds of this sort has been synthesized (and others are being constantly added). In this SBIR, the company will rigorously evaluate these novel compounds for topoisomerase targeting efficacy in vivo using defined model cells lines and in vitro using purified enzymes. This strategy for rational polyamine-topoisomerase drug design will reveal the most effective agents for cancer cell killing while minimizing damage to normal cells. PUBLIC HEALTH RELEVANCE: The development of targeted cancer therapies would be a clear advance in the treatment of cancer. Since cancer costs in the U.S. were nearly 1.4 million lives and $210 billion in 2005, it makes both medical and economic sense to invest in new pharmaceutical technologies. Smart drugs, which can selectively target and kill cancers, would begin to address this important public health issue.