Colon Cancer Prevention with Phospho-Sulindac

描述（由申请人提供）：联合化学预防的一项重大进展是使用舒林酸加二氟甲基鸟氨酸（DFMO），最近证明可将所有人类结肠腺瘤的复发率降低69%，晚期腺瘤的复发率降低92%。DFMO抑制鸟氨酸脱羧酶，该酶催化多胺合成的限速步骤，而sulindac刺激多胺乙酰化和出口。最终的结果是减少多胺水平，从而抑制癌细胞的生长。然而，舒林达克有明显的副作用：胃肠道（20%）；CNS(10%)，皮疹和瘙痒（5%），肝酶升高。因此，有必要开发更安全、更有效的药物。我们已经合成了一种新型的sulindac衍生物phospho-sulindac，其抑制人类结肠癌细胞生长的效力是传统sulindac的14倍以上，并且根据体外毒理学评估和动物研究显示比传统sulindac更安全。根据初步数据，我们的假设是：phospho-sulindac是一种有效、安全的化学预防药物，可与DFMO联用预防结肠癌，且联用效果优于常规的sulindac。为了验证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特性：效力、与DFMO的协同作用和对细胞动力学的影响。2)确定phospho-sulindac的作用机制，重点关注其对活性氧（reactive oxygen species， ROS）、化学预防药物作用的关键早期介质以及多胺等依赖信号通路的影响。3)在结肠癌动物模型（小鼠和异种移植）中确定磷酸磺林酸加DFMO对肠道癌变的影响，并在这些动物模型中验证关键的机制发现。这些目的将评估磷酸舒林酸药理作用的重要参数；探讨其作用机制；并为其人体应用所需的全面临床前评估奠定基础。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磺胺酸衍生物，磷酸磺胺酸，它比传统的磺胺酸更有效，更安全。我们建议评价磷酸舒林酸联合二氟甲基鸟氨酸（DFMO）预防结肠癌的作用。这是基于最近证明的常规舒林酸加DFMO能够将所有人类结肠腺瘤的复发率降低69%，晚期腺瘤的复发率降低92%。然而，传统的舒林酸有明显的副作用：胃肠道（20%）；CNS(10%)，皮疹和瘙痒（5%），肝酶升高。我们预计磷-舒林达将比舒林达更安全、更有效。拟议的工作将有助于其临床前评估，这是在人体中进行试验所必需的。

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.