Development of a novel agent for lung cancer prevention

描述（由申请人提供）：肺癌是美国癌症相关死亡的主要原因。尽管确定了几种预防药物和策略，但肺癌的最佳预防尚未实现。因此，需要更有效的药物，既能安全地实现预防，又不会产生严重的副作用。新型化合物是对已建立的化学预防药物的合理修饰，具有类似的作用机制，但具有增强的效力，降低的毒性和较低的剂量要求，可能在临床上更有意义。最近，我们开发了高度创新的杂交分子，p-XS-Asp和p-XS-Ibu，通过结合两种已知的化学预防药物，即1,4-苯基双（亚甲基）硒酸盐（p-XSC）和非甾体抗炎药（NSAIDs）阿司匹林和布洛芬，分别设计成肺癌预防的潜在药物。这些药物的优势是双重的：(i)联合p- XSC-NSAID混合药物将产生类似于p- xsc的活性p- xseh推定代谢物，但没有与氰化氢（HCN）相关的毒性；HCN作为副产物在p-XSC代谢中释放，但不会在p-XS-NSAID代谢中形成，并且（ii）新型药物通过释放相应的NSAID发挥作用，从而增强了杂交分子的整体化学预防功效。我们的初步研究支持这一假设，并确定p-XS-Asp是最有效的口服生物利用剂。该项目的总体目标是验证p-XS-Asp作为肺癌化学预防剂的潜力。我们假设p-XS-Asp会在体内裂解释放活性的p-XSeH，而不是释放不需要的HCN，而是释放阿司匹林，从而使其毒性更小，效力更强，比p-XSC或阿司匹林单独使用。本研究的目的是通过A/J小鼠肺癌模型测试p-XS-Asp抑制肺肿瘤发展的功效，并开始评估该药物显示其活性的机制。具体目的是：1)评价p-XS-Asp在nnk诱导的肺癌中的化学预防作用；2)评价p-XS-Asp在nnk诱导的肿瘤发生中的化学预防作用相关机制。我们将采用实验方法确定膳食p-XS-Asp的最大耐受剂量（MTD），并评估其对A/J小鼠腹腔注射1剂量10¿mol生理盐水NNK的抑制肿瘤发展的有效性。此外，为了开始建立机制，我们将使用肝微粒体进行其代谢，以确定p-XS-Asp是否会分裂成活性代谢物p-XSeH和阿司匹林，并评估cox -2介导的促有丝分裂MAPK和促生存PI3K/AKT信号通路，这些信号通路已知会受到p-XSC和/或阿司匹林的影响。这些研究将开始确定p-XS-Asp作为肺癌预防剂的潜力。从长远来看，p-XS- Asp作为一种有效和安全的药物将减少发生肺癌的机会，特别是在吸烟者/前吸烟者中，从而直接降低死亡率。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer related deaths in the United States. Despite the identification of several preventive agents and strategies, optimal prevention of lung cancer has not been achieved. More effective agents are therefore required that would safely achieve prevention without drastic side effects.Novel compounds which are rational modifications of well-established chemopreventive agents and follow a similar mechanism of action, but with enhanced potency, reduced toxicity, and lower dose requirement, may be clinically more relevant. Recently, we developed highly innovative hybrid molecules, p-XS-Asp and p-XS-Ibu, designed by conjugating two well known chemopreventive agents i.e. 1,4-phenylenebis(methylene)seleno- cyanate (p-XSC) and nonsteroidal anti-inflammatory drugs (NSAIDs) aspirin and ibuprofen, respectively, as potential agents for lung cancer prevention. The advantage of these agents is two-fold: (i) the combined p- XSC-NSAID hybrid drugs would generate the active p-XSeH putative metabolite similar to p-XSC but without the toxicity related to hydrogen cyanide (HCN); HCN is released as a side product on p-XSC metabolism but would not form in p-XS-NSAID metabolism, and (ii) the novel agents would function through releasing the corresponding NSAID, thus enhancing the overall chemopreventive efficacy of the hybrid molecule. Our preliminary studies supported this assumption and identified p-XS-Asp as the most potent and orally bioavailable agent. The overall goal of this project is to validate the potential of p-XS-Asp as a lung cancer chemopreventive agent. We hypothesize that p-XS-Asp would cleave in vivo to release the active p-XSeH, not releasing undesired HCN but aspirin, thus making it less toxic and more potent than p-XSC or aspirin alone. The objective of this proposal is to test the efficacy of p-XS-Asp for inhibiting lung tumor development using the A/J mouse lung cancer model and to begin evaluating the mechanism by which this agent exhibits its activity. The specific aims are: 1) evaluate the chemopreventive efficacy of p-XS-Asp in NNK-induced lung cancer, and 2) evaluate the mechanism of action(s) associated with chemopreventive effects of p-XS-Asp in NNK-induced tumorigenesis. We will use the experimental approach of determining the maximum tolerated dose (MTD) of dietary p-XS-Asp and evaluating its effectiveness for inhibiting tumor development in A/J mice injected intraperitonealy with one dose of 10 ¿mol NNK in saline. Furthermore, to begin establishing the mechanism, we will carry out its metabolism using liver microsomes to establish if p-XS-Asp will cleave into active metabolites p-XSeH and aspirin, and evaluate COX-2-mediated pro-mitogenic MAPK and pro-survival PI3K/AKT signaling pathways, which are known to be influenced by p-XSC and/or aspirin. These studies will begin establishing the potential of p-XS-Asp as lung cancer preventive agent. Long term, validation of p-XS- Asp as an effective and safe agent would reduce the chances of developing lung cancer, particularly, in smokers/former smokers thereby directly decreasing the mortality incidence.