Development of a novel agent for lung cancer prevention

开发一种新型肺癌预防剂

基本信息

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
项目类别：
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

项目摘要

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）：在美国，肺癌是癌症相关死亡的主要原因。尽管已经确定了多种预防药物和策略，但尚未实现肺癌的最佳预防，因此需要更有效的药物。安全地实现预防而没有严重的副作用。最近，我们高度关注新化合物，它们是成熟化学预防剂的改进，遵循类似的作用机制，但具有增强的效力、降低的毒性和较低的剂量需求。发达创新的混合分子 p-XS-Asp 和 p-XS-Ibu，通过结合两种众所周知的化学预防剂而设计，即 1,4-亚苯基双（亚甲基）硒氰酸盐 (p-XSC) 和非甾体抗炎药 (NSAID)阿司匹林和布洛芬分别作为预防肺癌的潜在药物，这些药物的优点有两个：（i）联合使用。 XSC-NSAID 混合药物会产生与 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-XSC 中形成； XS-NSAID 代谢，以及 (ii) 新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了这一点。 p-XS-Asp 作为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。我们发现 p-XS-Asp 在体内会裂解。释放活性 p-XSeH，不释放不需要的 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。该提案的目的是测试其功效。 p-XS-Asp 使用 A/J 小鼠肺癌模型抑制肺部肿瘤发展，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 的化学预防功效。在 NNK 诱导的肺癌中，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制。 (MTD) 膳食 p-XS-Asp 并评估其在腹膜内注射一剂 10 ¿ 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 介导的亲-已知受 p-XSC 和/或阿司匹林影响的促有丝分裂 MAPK 和促存活 PI3K/AKT 信号通路。 p-XS-Asp 作为肺癌预防剂。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。