Research Project
2015432
Mucositis is a common, dose-limiting complication in patients receiving cancer chemotherapy, which derives from damage to the epithelial cell layer. The resulting interruption in the integrity of the oral epithelium provides a systemic portal of entry for the numerous microorganisms that populate the mouth and the oral cavity is a frequently identifiable source of sepsis in the granulocytopenic cancer patient. Transforming growth factors-beta (TGF-beta's) have been shown significantly reducing the incidence, severity and duration of oral mucositis in hamsters. Here we propose to establish clinically relevant animal models for radiation- induced and for combined chemotherapy-radiation induced oral mucositis, using a standardized scoring system. In addition we propose to establish sensitive surrogate markers of tissue damage to be used for the evaluation of experimental mucositis and its pathophysiological basis. These include markers of inflammation (inducible nitric oxide synthase, interleukin-1beta and tumor necrosis factor-alpha), markers of cell damage (acid phosphatase and albumin), markers of cell stress (heat shock protein-9O) and a cell cycle marker (bromodeoxyuridine), which might aid in both animal and human studies of therapeutics for oral mucositis. Early markers which are predictive of impending mucositis would be particularly valuable. In Phase II, we propose to assess the dose and schedule dependence of TGF-beta3 in the amelioration of radiation- and chemotherapy-induced mucositis, using the mucositis models and surrogate marker systems developed in Phase I. The medial need and market potential for an effective agent which prevents or treats oral mucositis is substantial. PROPOSED COMMERCIAL APPLICATION: Oral mucositis is a painful and sometimes life-threatening complication observed in 20-40% of cancer patients receiving chemo and radio-therapy. The medical need and market potential for an effective therapeutant for this indication are large.
