Research Project
6176736
Mucositis is a common, dose-limiting complication in patients receiving cancer chemotherapy, which derives from damage to the epithelial cell layer. The oral cavity is a frequently identifiable source of sepsis in the granulocytopenic cancer patient. Transforming growth factors-beta (TGF-betas) have been shown significantly reducing the incidence, severity and duration of oral mucositis in hamsters. In Phase I we developed a robust animal model for radiation and combined chemotherapy/radiation in the Golden Syrian hamster. These models employed a fractionated radiation regimen to induce significant mucositis with little mortality and acceptable weight loss. Histological examination of the oral mucosa showed a similar morphologic appearance and time course when compared to human clinical samples. A series sensitive surrogate markers of tissue damage to evaluate experimental mucositis and its pathophysiological basis were established, including markers of inflammation, markers of epithelial layer water loss, markers of cell stress and cell cycle markers. These marker studies were correlated with the histologic evaluation of the mucosal tissue over a time course following cytotoxic therapy. We propose to assess the dose, schedule and route of administration dependence of TGF-beta3 in the amelioration of radiation-induced mucositis, using the mucositis models and surrogate marker systems developed in Phase I. The medial meed 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 percent of cancer patients receiving chemo and radio-therapy. The medical need and market potential for an effective therapeutant for this indication are large.
