A novel compound for colorectal cancer prevention

一种预防结直肠癌的新型化合物

• 批准号: 8890808
• 负责人: ARUN K SHARMA
• 金额: $ 7.44万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-11 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8890808
• 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; Health; 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; colon carcinogenesis; colorectal cancer prevention; cyclooxygenase 1; design; efficacy testing; in vivo; indexing; innovation; mortality; mouse model; novel; pre-clinical; preclinical study; prevent; selenocyanate; selenol

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CRC的最佳预防。因此，需要更有效的药物，可以安全地实现预防，而不会产生严重的副作用。新型化合物是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，降低的毒性和较低的剂量要求，可能在临床上更相关。最近，我们开发了高度创新的口服生物可利用的杂合分子p-XS- Asp，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）-硒代氰酸酯（p-XSC）和非甾体抗炎药阿司匹林缀合而设计，作为潜在的CRC预防剂。p-XSC和阿司匹林都显示出作为CRC化学预防剂的前景。混合代理的优点是双重的：（i）组合的p-XSC-Asp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，所述氰化氢作为p-XSC代谢的副产物释放，但不会在p-XS-Asp代谢中形成，和（ii）新试剂将通过释放阿司匹林起作用，从而增强杂合分子的总体化学预防功效。本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。具体目标是：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.评价与p-XS-Asp在AOM诱导的致癌作用中的化学预防作用相关的作用机制。我们将使用实验方法评价p-XS-Asp在皮下注射F344大鼠中抑制异常隐窝病灶（ACF）发展的有效性。AOM，每周一次，持续2周，剂量率为每周15 mg/kg体重。此外，为了开始建立该机制，我们将使用大鼠肝微粒体进行p-XS-Asp的代谢，并评估其相对于p-XSC和阿司匹林对结直肠组织中细胞凋亡和增殖标志物、信号通路如PI 3 K/AKT和MAPK、NF-kB以及考克斯-1和考克斯-2表达的影响，并测定不同处理组大鼠的血浆PGE 2水平。这些研究将开始确立p-XS-Asp作为结直肠癌预防剂的潜力。从长远来看，p-XS-Asp作为一种有效和安全的药物将减少结直肠癌的发生，从而直接降低死亡率。