Development of a novel agent for lung cancer prevention

开发一种新型肺癌预防剂

• 批准号: 8507667
• 负责人: ARUN K SHARMA
• 金额: $ 7.11万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-09 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8507667
• 关键词: A/J Mouse; Adverse effects; Affect; Animal Model; Aspirin; Bioavailable; Biological Assay; Biological Models; Butanones; Cancer Etiology; Cancer Model; Carcinogens; Cessation of life; Chemoprevention; Chemopreventive Agent; Cleaved cell; Clinical; Clinical Research; Clinical Trials; DNA Adducts; Data; Development; Diet; Disease; Dose; Effectiveness; Evaluation; Excretory function; Exhibits; Future; Goals; Human; Hybrids; Hydrogen Cyanide; Ibuprofen; Incidence; Individual; Intake; Investigation; Lead; Link; Literature; Liver Microsomes; Lung; Lung Neoplasms; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of lung; Maximum Tolerated Dose; Mediating; Metabolic; Metabolism; Minor; Modification; National Cancer Institute; Non-Steroidal Anti-Inflammatory Agents; PI3K/AKT; PTGS2 gene; Pharmaceutical Preparations; Prevention; Prevention strategy; Preventive; Prodrugs; Property; Research; Saline; Side; Signal Pathway; Signal Transduction; Smoker; Smoking Prevention; Structure; Structure of parenchyma of lung; Testing; Therapeutic Uses; Time; Tobacco use; Tobacco-Associated Carcinogen; Toxic effect; United States; Validation; Work; absorption; analog; base; cancer type; carbene; carcinogenesis; design; drug metabolism; efficacy testing; enzyme activity; high risk; in vivo; indexing; innovation; lung cancer prevention; mortality; novel; pre-clinical; preclinical study; prevent; selenocyanate; selenol; smoking cessation; tumor; tumorigenesis; yeast two hybrid system

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.

描述（由申请人提供）：肺癌是美国癌症相关死亡的主要原因。尽管已经确定了几种预防药物和策略，但尚未实现肺癌的最佳预防。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。新型化合物是对成熟化学预防药物的合理改良，遵循类似的作用机制，但具有增强的效力、降低的毒性和更低的剂量需求，可能在临床上更有意义。最近，我们开发了高度创新的混合分子，p-XS-Asp 和 p-XS-Ibu，通过结合两种众所周知的化学预防剂，即 1,4-亚苯基双（亚甲基）硒氰酸酯（p-XSC）和非甾体抗炎药（NSAID）阿司匹林和布洛芬，分别作为潜在的药物 肺癌的预防。这些药物的优点有两个：(i) 组合的 p-XSC-NSAID 混合药物将产生与 p-XSC 类似的活性 p-XSeH 推定代谢物，但没有与氰化氢 (HCN) 相关的毒性； HCN 作为 p-XSC 代谢的副产物释放，但不会在 p-XS-NSAID 代谢中形成，并且（ii）新型药物将通过释放相应的 NSAID 发挥作用，从而增强混合分子的整体化学预防功效。我们的初步研究支持了这一假设，并确定 p-XS-Asp 是最有效的口服生物利用度药物。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 会在体内裂解并释放活性 p-XSeH，而不是释放不需要的 HCN，而是释放阿司匹林，从而使其比单独的 p-XSC 或阿司匹林毒性更小且更有效。该提案的目的是使用 A/J 小鼠肺癌模型测试 p-XS-Asp 抑制肺肿瘤发展的功效，并开始评估该药物发挥其活性的机制。具体目标是：1) 评估 p-XS-Asp 在 NNK 诱导的肺癌中的化学预防功效，2) 评估 p-XS-Asp 在 NNK 诱导的肿瘤发生中的化学预防作用相关的作用机制。我们将使用实验方法确定膳食 p-XS-Asp 的最大耐受剂量 (MTD)，并评估其在腹膜内注射一剂 10 µmol NNK 生理盐水的 A/J 小鼠中抑制肿瘤发展的有效性。此外，为了开始建立该机制，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 MAPK 和促生存 PI3K/AKT 信号通路，这些信号通路已知受 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，验证 p-XS-Asp 作为一种有效且安全的药物将减少患肺癌的机会，特别是吸烟者/前吸烟者，从而直接降低死亡率。