Chemoprevention of colon cancer by a novel COX-2 inhibitor

描述（由申请人提供）：我们研究的总体目标是评估Secoxib-1 GSH（一种新开发的塞来昔布的硒类似物）对结肠癌的化学预防作用。癌症是美国人的第二大死因。正常结肠细胞转化为恶性病变需要几个步骤，通常需要相当长的时间，平均为10-15年，因此为有效干预和预防提供了机会。然而，据估计，2012年仅在美国就有大约15万人被诊断为结直肠癌。环合加氧酶（COX）作为一种重要的分子靶点已被广泛研究，并成为抗癌新药筛选的重要靶点。COX选择性抑制剂（COXIBs）是一类选择性COX-2抑制剂，长期使用已显示出心脏毒性副作用。因此，迫切需要开发新的药物来预防结肠癌的发生。在这个修改后的申请中，我们将研究Secoxib-1GSH（一种新开发的塞来昔布的硒类似物）对结肠癌的抑制作用。在我们的初步研究中，Secoxib-1 GSH保留了选择性

DESCRIPTION (provided by applicant): Overall goal of our study is to evaluate the chemopreventive efficacy of Secoxib-1 GSH, a newly developed selenium analog of Celecoxib, against colon cancer. Cancer is the second leading cause of death among Americans. Conversion of normal colonic cells to malignant lesions requires several steps and often proceeds over considerable time periods, on average, 10-15 years, thus providing a window of opportunity for effective intervention and prevention. However, in 2012 it was estimated that in the United States alone about 150,000 people will be diagnosed with colorectal cancer. Earlier reports have established cyclooxygenase (COX) as an important molecular target for mechanistic studies and important target for new anticancer drugs screening. The long-term uses of COX selective inhibitor (COXIBs), a class of compounds that are selective COX-2 inhibitors, have shown cardio-toxic side effects. Therefore, there is an urgent need for the development of new agents for the prevention modality of colon cancer. In this revised application, we will investigate the inhibitory effects of Secoxib-1GSH, a newly developed selenium analog of Celecoxib, against colon cancer. In our preliminary studies, Secoxib-1 GSH has retained the selective shown protective effect to these cells. We hypothesize that Secoxib-1 GSH, having minimal or no cardio-toxicity; having inhibitory effects on multiple mechanistic pathways including inhibition of COX-2, PI3K/Akt, and NFkB will be a safe and potent chemopreventive agent for prevention of colon cancer. To test our hypothesis, we propose to determine maximum tolerated dose (MTD) of Secoxib-1 GSH when fed in the diet to male F344 rats for the assessment of major organ related systemic toxicity. Based on the outcome from the MTD study, we will examine and compare the inhibitory potency of Secoxib-1 GSH with Celecoxib in male F344 rats against 1, 2-Dimethylhydrazine (DMH) induced mucin depleted foci (MDF), colonic aberrant crypt foci (ACF), preneoplastic lesions; and tumor burden in rats. We will also examine the effects of Secoxib-1 GSH on the important mechanistic pathways of colon cancer in the MDF, ACF, and tumor samples from male F344 rats.