iNOS/Akt Inhibotor for Colon Cancer Chemoprevention

描述(由申请人提供)： 该项目的总体目标是在硒的基础上开发基于iNOS/PI3激酶抑制剂的机制，以提高对抗结肠癌预防的效力。据报道，有几种诱导型一氧化氮合酶抑制剂用于预防癌症。其中S、S的1，4-亚苯基-双(1，2-乙二基)双异硫脲(PBIT)是体内抑制结肠迷走性隐窝病灶和预防食道癌的有效药物。结直肠癌(CRC)是包括美国在内的西方世界最常见的人类恶性肿瘤之一。预防性治疗是治疗癌症的一种很有前途的方法，它有可能成为结直肠癌控制的主要组成部分。由于正常结肠细胞向恶性细胞的转化需要几个步骤，通常需要相当长的时间，因此有足够的机会开发可能在癌症不同阶段发挥作用的基于机制的预防性药物。最近的研究表明，PI3激酶信号转导(Akt表达)和iNOS在人结肠肿瘤以及啮齿动物模型中过表达的重要性为开发选择性抑制两条主要信号通路提供了基础。开发的新试剂名为S，S的1，4-亚苯基-双(1，2-乙二基)双异硒脲(PBISe)，是一种同构型的硒类似物。我们实验室的初步结果表明，在MTS试验中测试的四种结肠癌细胞株中，PBISe的效力是PBIT的25倍。Western印迹分析显示，PAKT和Akt2水平降低，下游pPRAS40水平伴随着裂解PARP的增加，PARP是一种表明暴露于PBISe而不是PBIT时PI3激酶活性降低的细胞凋亡标志物。基于假设和支持性的初步数据，我们希望在可能用于人类临床试验之前，进一步开发PBISe用于临床前疗效和药理学研究。我们特别建议在雄性F344大鼠模型上研究PBISe静脉注射和饮食给药的药代动力学、药效学、组织分布和体内最大耐受量(MTD)。

DESCRIPTION (provided by applicant): The Overall objective of the project is to develop mechanism based iNOS / PI3 kinase inhibitor in addition to selenium to increase potency against colon cancer prevention. Several iNOS inhibitors have been reported for prevention of cancers. One such agents, S,S'-1,4-phenylene-bis(1,2- ethanediyl)bis-isothiourea (PBIT) was effective inhibitor in vivo for colonic Aberrant crypt foci (ACF) and for prevention of esophageal cancer. Colorectal cancer (CRC) is one of the most common human malignancies in the western world, including United States. Preventive therapies are promising approach for treatment of cancer, and it has a potential to be a major component of colorectal cancer control. Due to the fact that conversion of normal colonic cells to malignant cells requires several steps and often proceeds over considerable time period, therefore there is an ample opportunity for the development of mechanism based preventive agents that may act at different stages of cancer. Recent studies have shown the importance of PI3 kinase signaling (Akt expression) and iNOS over-expressed in human colon tumors as well as in rodent models provides the basis to develop selective inhibitor of two major signaling pathways. The novel agent developed is called S,S'-1,4-phenylene-bis(1,2- ethanediyl)bis-isoselenourea (PBISe), an isosteric selenium analog of PBIT. Preliminary results from our laboratory indicate that PBISe is >25 fold more potent than PBIT in four colon cancer cell lines tested in MTS assay. Western blot analysis showed decreased pAkt and Akt2 levels, and downstream pPRAS40 levels accompanied by an increase in cleaved PARP, an apoptosis markers demonstrating decreased PI3 kinase activity upon exposure to PBISe but not PBIT. Based on hypothesis and supportive preliminary data, we want to further develop PBISe for preclinical efficacy and pharmacological studies prior to the possible use in human clinical trials. We specifically propose to investigate the pharmacokinetics, pharmacodynamics, tissue distribution, and in vivo maximum tolerated dose (MTD) of PBISe administered by intravenous injection or diet in male F344 rat model.