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（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，但尚未实现肺癌的最佳预防。因此，需要更有效的药物，将安全地实现预防而没有剧烈的副作用。新的化合物，是合理的修改完善的化学预防剂，并遵循类似的作用机制，但具有增强的效力，降低毒性，和较低的剂量要求，可能是临床上更相关。最近，我们开发了高度创新的杂化分子，p-XS-Asp和p-XS-Ibu，其通过将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）分别与非甾体抗炎药（NSAID）阿司匹林和布洛芬缀合而设计，作为潜在的肺癌预防剂。这些药剂的优点是双重的：（i）组合的p-XSC-NSAID杂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p-XSC代谢的副产物释放，但不会在p-XS-NSAID代谢中形成，和（ii）新药剂将通过释放相应的NSAID发挥作用，从而增强杂合分子的总体化学预防功效。我们的初步研究支持了这一假设，并确定p-XS-Asp为最有效和口服生物利用度最高的药物。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将在体内裂解以释放活性p-XSeH，不释放不需要的HCN，而是释放阿司匹林，从而使其毒性更小并且比单独的p-XSC或阿司匹林更有效。本提案的目的是使用A/J小鼠肺癌模型测试p-XS-Asp抑制肺肿瘤发展的功效，并开始评价该药剂显示其活性的机制。具体目标是：1）评价p-XS-Asp在NNK诱导的肺癌中的化学预防功效，和2）评价与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。我们将使用实验方法确定膳食p-XS-Asp的最大耐受剂量（MTD），并评估其对腹膜内注射一剂10 μ mol NNK盐水溶液的A/J小鼠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是否将裂解成活性代谢物p-XSeH和阿司匹林，并评估已知受p-XSC和/或阿司匹林影响的考克斯-2介导的促有丝分裂MAPK和促存活PI 3 K/AKT信号通路。这些研究将开始确立p-XS-Asp作为肺癌预防剂的潜力。长期而言，p-XS- Asp作为一种有效且安全的药物的验证将降低发生肺癌的机会，特别是在吸烟者/前吸烟者中，从而直接降低死亡率。 公共卫生相关性：到目前为止，还没有有效的药物可用于预防肺癌，其中约90%的病例归因于烟草使用。本文提出的研究将开始验证我们最近开发的杂合剂p-XS-Asp作为针对NNK诱导的致癌作用的有效且安全的化学预防剂，并开始阐明化学预防的潜在机制。如果有效，这项研究将揭示一种有前途的药物，在不久的将来，可以证明能够预防吸烟者的肺癌发展。