Development of a novel agent for lung cancer prevention

描述(申请人提供)：肺癌是美国癌症相关死亡的主要原因。尽管已经确定了几种预防药物和策略，但尚未实现对肺癌的最佳预防。因此，需要更有效的药物来安全地实现预防，而不会产生严重的副作用。新型化合物是对已有的化学预防药物的合理修改，遵循类似的作用机制，但具有更强的效力、降低毒性和更低的剂量要求，可能更具有临床意义。最近，我们开发了高度创新的杂化分子p-XS-Asp和p-XS-IBu，它们是通过将两种著名的化学预防药物-1，4-亚甲基双(亚甲基)硒氰酸酯(p-XSC)和非甾体抗炎药(NSAIDs)阿司匹林和布洛芬分别连接起来设计的，作为潜在的肺癌预防药物。这些药物的优点有两个：(I)组合p-XSC-NSAID杂化药物将产生与p-XSC相似的活性p-XSeH推定代谢物，但没有氰化氢(HCN)相关的毒性；HCN作为p-XSC代谢的副产物释放，但不会在p-XS-NSAID代谢中形成，(Ii)新药物将通过释放相应的NSAID发挥作用，从而提高杂化分子的整体化学预防效果。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作为肺癌化学预防药物的潜力。我们假设p-XS-Asp会在体内裂解以释放活性的p-XSeH，而不是释放不需要的HCN，而是释放阿司匹林，从而使其毒性更低，比单独使用p-XSC或阿司匹林更有效。本提案的目的是利用A/J小鼠肺癌模型测试p-XS-Asp抑制肺癌发展的有效性，并开始评估该药显示其活性的机制。其具体目的是：1)评价p-XS-Asp对NNK诱导的肺癌的化学预防作用；2)评价p-XS-Asp对NNK诱导的肺癌的化学预防作用机制(S)。我们将采用实验方法，测定饮食中p-XS-Asp的最大耐受量(MTD)，并评价其对A/J小鼠的抑制肿瘤发展的有效性。此外，为了开始建立这种机制，我们将使用肝脏微粒体进行其代谢，以确定p-XS-Asp是否会裂解成活性代谢物p-XSeH和阿司匹林，并评估COX-2介导的促有丝分裂的MAPK和促生存的PI3K/AKT信号通路，这是已知受p-XSC和/或阿司匹林影响的。这些研究将开始确定p-XS-Asp作为肺癌预防药物的潜力。从长远来看，确认p-XS-Asp是一种有效和安全的药物将减少患肺癌的机会，特别是在吸烟者/以前吸烟者中，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.