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.
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.
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