Colon Cancer Prevention with Phospho-Sulindac

描述（由申请人提供）：联合化学预防的一个重要进展是使用舒林酸加二氟甲基鸟氨酸（DFMO），最近证实其可将所有人结肠腺瘤的复发率降低69%，将晚期腺瘤的复发率降低92%。DFMO抑制鸟氨酸脱羧酶，其催化多胺合成中的限速步骤，而舒林酸刺激多胺乙酰化和输出。最终结果是多胺水平降低，导致癌细胞生长受到抑制。然而，舒林酸具有显著的副作用：胃肠道（20%）; CNS（10%），皮疹和瘙痒（5%），以及肝酶升高。因此，需要开发更安全和更有效的药剂。我们已经合成了磷酸-舒林酸，一种新的舒林酸衍生物，其在抑制人结肠癌细胞生长方面比常规舒林酸有效超过14倍，并且基于体外毒理学评价和动物研究，似乎比常规舒林酸安全得多。我们的假设得到了初步数据的支持，即磷酸-舒林酸是一种有效且安全的化学预防剂，可以与DFMO联合用于预防结肠癌，并且这种联合上级使用常规舒林酸的联合。为了评估这一假设并描述相关机制，我们提出了三个具体目标：1）评估与化学预防相关的磷酸-舒林酸的体外性质：效力、与DFMO的协同作用和对肿瘤的作用。2)确定磷酸舒林酸的作用机制，重点关注其对活性氧（ROS）的影响，ROS是化学预防剂作用的关键早期介质，以及对依赖性信号传导途径（包括多胺）的影响。3)在结肠癌动物模型（Min小鼠和异种移植物）中确定磷酸舒林酸加DFMO对肠道致癌作用的影响，并在这些动物模型中验证关键机制发现。这些目标将评估磷酸-舒林酸药理作用的重要参数;探索其作用机制;并为其在人体应用所需的彻底临床前评价奠定基础。公共卫生相关性：开发有效和安全的化学预防剂是一个高度优先事项。我们合成了一种新的舒林酸衍生物磷酸化舒林酸，它比传统的舒林酸更有效和安全。我们建议评估磷酸舒林酸与二氟甲基鸟氨酸（DFMO）联合预防结肠癌。这是基于最近证实的常规舒林酸加DFMO将所有人类结肠腺瘤的复发降低69%和将晚期腺瘤的复发降低92%的能力。然而，传统的舒林酸具有显著的副作用：胃肠道（20%）、CNS（10%）、皮疹和瘙痒（5%）以及肝酶升高。我们预计磷酸-舒林酸将比舒林酸更安全和更有效。拟议的工作将有助于其临床前评价，这是需要磷酸-舒林酸在人体中进行测试。

DESCRIPTION (provided by applicant): A significant development in combination chemoprevention is the use of sulindac plus difluoromethylornithine (DFMO), which was recently demonstrated to reduce the recurrence of all human colon adenomas by 69% and of advanced adenomas by 92%. DFMO inhibits ornithine decarboxylase, which catalyzes the rate-limiting step in polyamine synthesis, while sulindac stimulates polyamine acetylation and export. The end result is reduced polyamine levels leading to suppressed growth of cancer cells. Sulindac, however, has significant side effects: gastrointestinal (20%); CNS (10%), skin rash and pruritus (5%), and elevations of hepatic enzymes. Thus there is a need to develop safer and more effective agents. We have synthesized phospho-sulindac, a novel derivative of sulindac, that is over >14-fold more potent than conventional sulindac in inhibiting the growth of human colon cancer cells, and appears much safer than conventional sulindac based on in vitro toxicological evaluation and animal studies. Our hypothesis, supported by preliminary data, is that phospho-sulindac is an effective and safe chemopreventive agent that can be combined with DFMO for the prevention of colon cancer and that such combination is superior to the one using conventional sulindac. To evaluate this hypothesis and delineate the relevant mechanisms, we propose three specific aims: 1) Evaluate in vitro properties of phospho-sulindac that are relevant to chemoprevention: potency, synergy with DFMO and effect on cytokinetics. 2) Determine the mechanism of action of phospho-sulindac focusing on its effect on reactive oxygen species (ROS), key early mediators of the effect of chemopreventive agents, and on dependent signaling pathways including polyamines. 3) Determine in animal models of colon cancer (Min mice and xenografts) the effect of phosphosulindac plus DFMO on intestinal carcinogenesis and verify in these animal models key mechanistic findings. These aims will assess important parameters of the pharmacological action of phospho-sulindac; explore its mechanism of action; and set the stage for its thorough preclinical evaluation that is required for its human application. PUBLIC HEALTH RELEVANCE: The development of effective and safe chemopreventive agents represents a high priority. We have synthesized a new derivative of sulindac, phospho-sulindac, which is more effective and safer than conventional sulindac. We propose to evaluate phospho-sulindac in combination with difluoromethylornithine (DFMO) for the prevention of colon cancer. This is based on the recently demonstrated ability of conventional sulindac plus DFMO to reduce the recurrence of all human colon adenomas by 69% and of advanced adenomas by 92%. Conventional sulindac, however, has significant side effects: gastrointestinal (20%); CNS (10%), skin rash and pruritus (5%), and elevations of hepatic enzymes. We anticipate that phospho-sulindac will be safer and more effective than sulindac. The proposed work will contribute to its preclinical evaluation, which is required for phospho-sulindac to be tested in humans.