A novel compound for colorectal cancer prevention

描述(申请人提供)：结直肠癌(CRC)是美国第二大癌症死亡原因。尽管确定了几种预防性药物和战略，但尚未实现对CRC的最佳预防。因此，需要更有效的制剂来安全地实现预防，而不会产生严重的副作用。对已有的化学预防药物进行合理修改并遵循类似的作用机制，但具有增强效力、降低毒性和较低剂量要求的新型化合物，可能在临床上更具相关性。最近，我们开发了高度创新的口服生物可用杂化分子p-XS-Asp，它是通过将两种著名的化学预防药物1，4-亚甲基双(亚甲基)-硒氰酸酯(p-XSC)和非甾体抗炎药物阿司匹林偶联而设计的，作为潜在的预防结直肠癌的药物。P-XSC和阿司匹林都显示出作为结直肠癌化疗保护剂的前景。杂化制剂的优点有两个：(I)组合的p-XSC-Asp将产生与p-XSC相似的活性p-XSeH推定代谢物，但没有氰化氢(HCN)相关的毒性，它在p-XSC代谢中作为副产物释放，但不会在p-XS-Asp代谢中形成，(Ii)新制剂通过释放阿司匹林发挥作用，从而提高杂化分子的整体化学预防效果。本项目的总体目标是验证p-XS-Asp作为结肠癌化学预防药物的潜力。我们假设p-XS-Asp会在体内裂解以释放活性的p-XSeH，而不是释放不需要的HCN，而是释放阿司匹林，从而使其毒性更低，比单独使用p-XSC或阿司匹林更有效。本实验的具体目的是：1.测定p-XS-Asp对F344大鼠结直肠癌变模型的化学预防作用；2.评价p-XS-Asp对AOM诱导的大鼠结直肠癌的化学预防作用机制(S)。我们将采用评价p-XS-Asp抑制F344大鼠SC注射后异常隐窝病灶(ACF)发展的实验方法。AOM，每周一次，连续两周，剂量率为每周15毫克/公斤体重。此外，为了开始建立机制，我们将利用大鼠肝微粒体进行p-XS-Asp的代谢，并评价其相对于p-XSC和阿司匹林对大肠组织中细胞凋亡和细胞增殖的标志物、PI3K/AKT和MAPK、NF-kB以及COX-1和COX-2表达的影响，并测定不同治疗组大鼠血浆PGE2水平。这些研究将开始确定p-XS-Asp作为结直肠癌预防药物的潜力。从长远来看，验证p-XS-Asp作为一种有效和安全的药物将减少发生结直肠癌的机会，从而直接降低死亡率。

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.