iNOS/Akt Inhibotor for Colon Cancer Chemoprevention

描述（由申请人提供）： 该项目的总体目标是开发除硒之外的基于iNOS /PI 3激酶抑制剂的机制，以增加对结肠癌预防的效力。已经报道了几种iNOS抑制剂用于预防癌症。S，S ′-1，4-亚苯基-双（1，2-乙二基）双异噻唑啉（PBIT）是一种有效的结肠异常隐窝灶（ACF）抑制剂，可用于预防食管癌。结直肠癌（Colorectal cancer，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。预防性治疗是一种很有前途的癌症治疗方法，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并且通常在相当长的时间段内进行，因此存在开发可在癌症的不同阶段起作用的基于机制的预防剂的充分机会。最近的研究表明PI 3激酶信号传导（Akt表达）和iNOS在人类结肠肿瘤以及啮齿动物模型中过表达的重要性为开发两种主要信号传导途径的选择性抑制剂提供了基础。所开发的新试剂被称为S，S '-1，4-亚苯基-双（1，2-乙二基）双异硒醚（PBISe），PBIT的电子等排硒类似物。来自我们实验室的初步结果表明，在MTS测定中测试的四种结肠癌细胞系中，PBISe比PBIT有效>25倍。蛋白质印迹分析显示pAkt和Akt 2水平降低，下游pPRAS 40水平伴随切割的PARP增加，PARP是一种细胞凋亡标志物，表明暴露于PBISe而非PBIT后PI 3激酶活性降低。基于假设和支持性初步数据，我们希望在可能用于人体临床试验之前，进一步开发PBISe用于临床前疗效和药理学研究。我们特别提出研究PBISe的药代动力学，药效学，组织分布，并在体内最大耐受剂量（MTD）通过静脉注射或饮食给予雄性F344大鼠模型。

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.