A novel compound for colorectal cancer prevention

一种预防结直肠癌的新型化合物

基本信息

批准号：
8786739
负责人：
ARUN K SHARMA
金额：
$ 7.45万
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：
2014
资助国家：
美国
起止时间：
2014-07-11 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8786739
关键词：
A/J Mouse Aberrant crypt foci Adverse effects Affect Animal Model Apoptosis Aspirin Bioavailable Biological Assay Body Weight Cause of Death Cell Proliferation Chemoprevention Chemopreventive Agent Cleaved cell Clinical Clinical Trials Colon Colon Carcinoma Colorectal Colorectal Cancer Data Development Dinoprostone Dose Dose-Rate Effectiveness Evaluation Excretory function Exhibits Future Goals Human Hybrids Hydrogen Cyanide Inbred F344 Rats Incidence Individual Inflammatory Intake Investigation Lead Link Literature Liver Microsomes Lung Neoplasms MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of lung Metabolic Metabolism Minor Modeling Modification NF-kappa B National Cancer Institute Non-Steroidal Anti-Inflammatory Agents PI3K/AKT PTGS2 gene Pharmaceutical Preparations Plasma Prevention Preventive Prodrugs Property Rattus Rectum Relative (related person)Research Side Signal Pathway Signal Transduction Structure Testing Therapeutic Uses Time Tissues Toxic effect United States Validation absorption base cancer type carbene carcinogenesis colon cancer cell line colorectal cancer prevention cyclooxygenase 1 design efficacy testing in vivo indexing innovation mortality mouse model novel pre-clinical preclinical study prevent public health relevance selenocyanate selenol

A/J Mouse Aberrant crypt foci Adverse effects Affect Animal Model Apoptosis Aspirin Bioavailable Biological Assay Body Weight Cause of Death Cell Proliferation Chemoprevention Chemopreventive Agent Cleaved cell Clinical Clinical Trials Colon Colon Carcinoma Colorectal Colorectal Cancer Data Development Dinoprostone Dose Dose-Rate Effectiveness Evaluation Excretory function Exhibits Future Goals Human Hybrids Hydrogen Cyanide Inbred F344 Rats Incidence Individual Inflammatory Intake Investigation Lead Link Literature Liver Microsomes Lung Neoplasms MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of lung Metabolic Metabolism Minor Modeling Modification NF-kappa B National Cancer Institute Non-Steroidal Anti-Inflammatory Agents PI3K/AKT PTGS2 gene Pharmaceutical Preparations Plasma Prevention Preventive Prodrugs Property Rattus Rectum Relative (related person)Research Side Signal Pathway Signal Transduction Structure Testing Therapeutic Uses Time Tissues Toxic effect United States Validation absorption base cancer type carbene carcinogenesis colon cancer cell line colorectal cancer prevention cyclooxygenase 1 design efficacy testing in vivo indexing innovation mortality mouse model novel pre-clinical preclinical study prevent public health relevance selenocyanate selenol

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项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second leading cause of death from cancer in the United States. Despite the identification of several preventive agents and strategies, optimal prevention of CRC 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 orally bioavailable hybrid molecule, p-XS- Asp, designed by conjugating two well-known chemopreventive agents i.e. 1,4-phenylene-bis(methylene)- selenocyanate (p-XSC) and nonsteroidal anti-inflammatory drug aspirin, as potential agents for CRC prevention. Both p-XSC and aspirin have shown promise as CRC chemopreventives. The advantage of the hybrid agent is two-fold: (i) the combined p-XSC-Asp would generate the active p-XSeH putative metabolite similar to p-XSC but without the toxicity related to hydrogen cyanide (HCN), that is released as a side product on p-XSC metabolism but would not form in p-XS-Asp metabolism, and (ii) the novel agent would function through releasing aspirin, thus enhancing the overall chemopreventive efficacy of the hybrid molecule. The overall goal of this project is to validate the potential of p-XS-Asp as colon 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 specific aims are to: 1. Determine the chemopreventive efficacy of p-XS-Asp in the F344 rat model of colorectal carcinogenesis; and 2. Evaluate the mechanism of action(s) associated with chemopreventive effects of p-XS-Asp in AOM-induced carcinogenesis. We will use the experimental approach of evaluating effectiveness of p-XS-Asp for inhibiting development of aberrant crypt foci (ACF) in F344 rats injected s.c. with AOM, once weekly for 2 weeks, at a dose rate of 15 mg/kg body weight per week. Furthermore, to begin establishing the mechanism, we will carry out metabolism of p-XS-Asp using rat liver microsomes, and evaluate its effect, relative to p-XSC and aspirin, on markers of apoptosis and cell proliferation, signaling pathways such as PI3K/AKT and MAPK, NF-kB and expression of COX-1 and COX-2 in colorectal tissues, and determine the plasma PGE2 levels of rats from different treatment groups. These studies will begin establishing the potential of p-XS-Asp as a colorectal cancer preventive agent. Long term, validation of p-XS-Asp as an effective and safe agent would reduce the chances of developing colorectal cancer thereby directly decreasing the mortality incidence.

描述（由申请人提供）：结直肠癌（CRC）是美国癌症死亡的第二大原因。尽管确定了几种预防剂和策略，但尚未实现最佳预防CRC。因此，需要更有效的药物，可以安全地实现预防，而无需剧烈的副作用。新颖的化合物是对良好的化学预防剂的合理修饰，并遵循类似的作用机理，但随着效力增强，毒性降低和剂量要求的增强，可能在临床上更相关。最近，我们开发了高度创新性的口服生物可利用杂化分子P-XS-ASP，它是通过结合两种众所周知的化学预防剂，即1,4-苯基烯双（亚甲基烯） - 硒烯酸（P-XSC）（P-XSC）和非甾体类抗炎药物抗药性药物，作为CRC的crc crccention。 P-XSC和阿司匹林都表现出有望作为CRC化学预防剂。混合剂的优势是两个倍：（i）P-XSC-ASP的组合会产生活跃的P-XSEH假定代谢物，类似于P-XSC，但没有与氢氰化物（HCN）相关的毒性，该毒性是在P-XSC代谢中以P-XSC代谢形成的，因此可以通过P-XSC的代理中的功能（II II II II II IN）发行（II），并且（II）是II II reprining the Extring nation and Neachering（II），并且（II II次）（II II次）（II II次）（II II次）（））杂化分子的总体化学预防疗效。该项目的总体目标是验证P-XS-ASP作为结肠癌化学预防剂的潜力。我们假设P-XS-ASP会在体内切割以释放活性P-XSEH，而不是释放出不希望的HCN，而是释放阿司匹林，从而使其比单独的p-XSC或阿司匹林更小的毒性和更有效。具体目的是：1。确定P-XS-ASP在结直肠癌发生的F344大鼠模型中的化学预防功效；和2。评估与P-XS-ASP在AOM诱导的癌变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评估P-XS-ASP在F344大鼠注射S.C.中抑制异常隐窝灶（ACF）的发育的有效性。使用AOM，每周一次一次，每周的体重为15 mg/kg体重。此外，要开始建立该机制，我们将使用大鼠肝脏微粒体对P-XS-ASP进行代谢，并评估其相对于P-XSC和p-XSC和阿司匹林的效果，对凋亡和细胞增殖的标志，信号传导途径，PI3K/AKT和MAPK，NF-KB，NF-KB，NF-KB和COX-1级别的COX-1级和COX-2级的pi3K/A.来自不同治疗组的大鼠。这些研究将开始确立P-XS-ASP作为结直肠癌预防剂的潜力。长期，对P-XS-ASP作为一种有效且安全的剂的验证将减少发生结直肠癌的机会，从而直接降低死亡率的发生。