CASPASE INHIBITORS FOR TREATMENT OF ORAL MUCOSITIS

DESCRIPTION: This initial R43 SBIR grant application proposes to assess the molecular mechanism of apoptosis and Caspase 1 mediated inflammation in buccal tissue due to radiation. This Phase I study has the following five Specific Aims: 1) Determine the time course and extent of apoptosis in the buccal mucosa due to radiation (XRT) or chemotherapy and develop cellular and molecular markers to evaluate Caspase inhibitor (CI) in this setting; 2) Basic pharmacokinetics level of Caspase inhibitor achieved, rate of penetration; 3) Determine CI's ability in reducing XRT or chemo-induced apoptosis; 4) Synthesize and characterize analogs of CI, CV 1153; and 5) Select an optimal pan-CI approach. There are two hypotheses stated, the first is that CI can reduce apoptosis due to XRT or chemotherapy and thus decrease the severity of oral mucositis by improving basal epithelial integrity. The second hypothesis is that the reduction in apoptosis by CI is due to, in addition to Caspase inhibition, decrease in Il-1 and TNF-alpha effects. For Specific Aims 1, Caspases 3 and 1 levels will be measured in tissue homogenate. Activation by cleavage will be assessed by Western blots. Apoptosis will be documented by histomorphology and TUNEL assay. 5-FU will be used in the chemotherapy part of the model. For Specific Aims 2, Franz chambers will be used to measure the flux of CV 1153. For Specific Aims 3, animals treated as per Specific Aims 1 will have CI applied and the buccal mucosa will be assayed directly for Caspase inhibition and reduction of apoptosis. For Specific Aims 4, 11 different analogs of and stereoisomers CV1153 will be synthesized. They will be used in Specific Aims 5, to optimize the reduction on oral mucositis. PROPOSED COMMERCIAL APPLICATION: Treatment of radiation or chemotherapy induced oral mucositis.