) oxide synthase; iNOS) has been implicated in the pathogenesis of various forms of inflammation. Chronic inflammation is a known risk factor for carcinogenesis. There are multiple lines of evidence implicating the iNOS/peroxynitrite pathway in the pathogenesis of intestinal inflammatory responses. In this proposal, we present evidence that (1) mercaptoethylguanidine (MEG), and its dimeric form, guanidinoethyldisulfide (GED) (lead compounds of the applicants' proprietary mercaptoalkylguanidine class of compound series) are promising nitric oxide synthase (NOS) inhibitors with selectivity for the inducible nitric oxide synthase isoform (iNOS), and with an additional peroxynitrite scavenger activity; and (2) that MEG and GED are compounds of appropriate therapeutic ratio, suitable for preclinical and clinical development for various forms of inflammation. These data, combined with (3) novel preliminary evidence implicating the role of the peroxynitrite/iNOS related mechanisms in the pathogenesis of intestinal polyposis lend strong support to the current proposal.
The aim of the proposed project is (1) to perform definitive in vivo studies in murine models of intestinal polyposis using the min/APC model in order to test whether GED can slow down or reverse the onset of the polyposis; and (2) to perform subchronic 90-day toxicity studies with GED in 2 species with the compounds in order to determine whether they are suitable for indications related to chronic intestinal inflammation/polyposis. The results of the present application will permit application for Phase 2 SBIR funding to support: completion of pre-clinical pharmaceutical testing (in order to complete advanced toxicity determinations, pathology, stability, pharmacokinetics), preparation of investigational drug application to the FDA, and a Phase I and II clinical trials.
The annual anticipated revenues for an effective therapeutic to prevent and treat intestinal polyposis is over $200 million in the US alone.
| Mabley, Jon G; Pacher, Pal; Bai, Peter et al. (2004) Suppression of intestinal polyposis in Apcmin/+ mice by targeting the nitric oxide or poly(ADP-ribose) pathways. Mutat Res 548:107-16 |
