Strong evidence supports the notion that chemoprevention has the potential to be a major component of colorectal cancer control. The prevention of cancer depends heavily on the development of safe and effective agents. NSAIDs prevent colorectal cancer but have two major limitations that preclude their large-scale application to prevent colorectal cancer: a) significant side effects, accounting per year for >15,000 deaths in the US;and b) limited efficacy, which, at best, is below 50%. A significant development in the prevention of colon cancer is the combined use of sulindac and difluoromethylornithine (DFMO);sulindac stimulates polyamine acetylation and export from the cell and DFMO inhibits the enzyme ornithine decarboxylase, which catalyzes the rate-limiting step in polyamine synthesis. The end result is reduced polyamine levels leading to suppressed growth of cancer cells. We have synthesized MDC-1231, a novel compound that a) when combined with DFMO prevents nearly completely colon cancer in preclinical models, and b) appears safe. Our hypothesis is that MDC-1231 is a safe and, when combined with DFMO, highly effective chemopreventive agent against colon cancer. To evaluate this hypothesis, we propose the following specific aims: 1) Determine the chemoprevention efficacy of MDC-1231 plus DFMO in human colon cancer xenografts in nude mice;2) Perform toxicity studies of MDC-1231 combined with DFMO;and 3) Study the metabolism, pharmacokinetics and pharmacodynamics of MDC-1231.
These aims will assess parameters that are essential to the development of MDC-1231. The results of the proposed studies will pave the way towards the completion of the preclinical development of MDC-1231 ultimately leading to a phase I clinical trial.
The anti-inflammatory drug sulindac combined with another compound (DFMO) prevents colon cancer. Sulindac, however, has significant side effects especially when given for prolonged periods of time. MDC-1123 is a novel sulindac-like drug that in preclinical studies appears safer and very effective in the prevention of colon cancer. The impact of this work on public health will be significant, as it will contribute to the development of an effective strategy for the control of colon cancer.
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| Huang, L; Mackenzie, Gg; Ouyang, N et al. (2011) The novel phospho-non-steroidal anti-inflammatory drugs, OXT-328, MDC-22 and MDC-917, inhibit adjuvant-induced arthritis in rats. Br J Pharmacol 162:1521-33 |
