Development of a novel agent for lung cancer prevention

开发一种新型肺癌预防剂

• 批准号: 8401402
• 负责人: ARUN K SHARMA
• 金额: $ 7.56万
• 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/8401402
• 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. PUBLIC HEALTH RELEVANCE: To date, there are no effective agents available for the prevention of lung cancer which, in ~90% of the cases, is attributed to tobacco use. The studies proposed here, will initiate validation of our recently developed hybrid agent p-XS-Asp as a potent and safe chemopreventive against NNK induced carcinogenesis and begin elucidating underlying mechanism of chemoprevention. If effective,this study would reveal a promising agent which, in near future, could prove capable of preventing lung cancer development in smokers.

描述（适用提供）：肺癌是美国与癌症相关死亡的主要原因。尽管确定了几种预防剂和策略，但尚未实现最佳预防肺癌。因此，需要更有效的药物可以安全地实现预防的情况下，而无需剧烈的副作用。新的化合物是对良好成熟的化学预防剂的合理修饰，并遵循类似的作用机制，但具有增强的效力，降低毒性和较低剂量需求，可能在临床上更相关。 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预防肺癌。这些药物的优点是两倍：（i）P-XSC-NSAID混合药的组合会产生活性的P-XSEH假定代谢物，类似于P-XSC，但没有与氰化氢（HCN）相关的毒性； HCN作为P-XSC代谢上的副产物发行，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来发挥作用，从而提高杂化分子的整体化学预防效率。我们的初步研究支持了这一假设，并确定了P-XS-ASP是最有潜在和口服的可生物利用剂。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会在体内清除以释放活性P-XSEH，而不是释放未释放的HCN，而是阿司匹林，从而使其具有比P-XSC或阿司匹林更少的毒性和更大的潜力。该建议的目的是测试P-XS-ASP使用A/J小鼠肺癌模型抑制肺部肿瘤发展的有效性，并开始评估该药物表现出其活性的机制。具体目的是：1）评估P-XS-ASP在NNK诱导的肺癌中的化学预防效率，以及2）评估与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理。我们将使用实验方法来确定饮食中P-XS-ASP的最大耐受剂量（MTD），并评估其在抑制A/J小鼠中抑制肿瘤发育的有效性，该A/J小鼠在腹膜内注射腹膜内注射了10剂10麦NNK。此外，为了开始建立该机制，我们将使用肝微粒体进行代谢，以确定P-XS-ASP是否将清除为活跃的代谢物P-XSEH和阿司匹林，并评估COX-2介导的Pro Mitogenogenic Mapk和Pro-Survival PI3K/AKT信号pation pro-Signing Pathways at ta Gibers Sccics和/或p-xscscscsic and/off-xscscscsic and/overscscscscsic and/off-xscscscscsic and/obived。这些研究将开始确立P-XS-ASP作为肺癌预防剂的潜力。从长远来看，对P-XS-ASP作为一种有效且安全的剂的验证将减少患肺癌的机会，特别是在吸烟者/前吸烟者中，从而直接降低死亡率的发生率。 公共卫生相关性：迄今为止，尚无有效预防肺癌的有效药物，在约90％的病例中，这归因于烟草的使用。此处提出的研究将启动我们最近开发的混合剂P-XS-ASP，作为针对NNK诱导的癌变的潜在且安全的化学预防，并开始阐明化学预防的潜在机制。如果有效，这项研究将揭示出一种承诺剂，在不久的将来，它可以证明能够防止吸烟者的肺癌发展。