There is considerable renewed interest in iododeoxyuridine (IdUrd) as a clinical sensitizer to radiation and certain chemotherapy drugs including bleomycin and cisplatinum. The overall goal of this proposal is to study potential mechanisms of differential IdUrd radio- and chemosensitization (bleomycin, cisplatinum) in human bladder and colon cancer cell lines compared to normal cells. While a major clinical strategy for IdURd radiosensitization is to select actively dividing, poorly radioresponsive tumors (like colon metastases to liver and bladder carcinomas) surrounded by non-dividing normal tissues (liver, bladder), it is clinically feasible that biochemical modulation of IdUrd cellular metabolism may lead to further differential sensitization. IdUrd may be an ideal sensitizer in human bladder cancer if it can sensitize both radiation and cisplatinum cytotoxicity. IdUrd is a thymidine (dThd) analog and competes with dThd for incorporation into DNA in dividing cells. IdUrd-DNA incorporation is felt to be necessary for both radio-and chemosensitization. Cellular metabolism of IdUrd (like dThd) involves two key regulatory enzymes, thymidine kinase (TK) and thymidylate synthase (TS). We will investigate the activity of these regulatory enzymes (purified and in vitro) to IdUrd in both tumor and normal cells. These approaches of biochemical modulation will be tested to increase IdUrd chemosensitization and radiosensitization. These approaches to IdUrd radiosensitization will also be tested using human tumor xenografts in nu/nu mice. Two tumor models will be studied including colon carcinoma metastases to liver and primary bladder carcinoma. Continuous infusions of IdUrd and other modulating drugs (e.g. 5'-AT, FdUrd, MTX) will be monitored by plasma pharmacokinetic studies. IdUrd-DNA incorporation into tumor and normal tissue will be determined by HPLC and flow cytometry techniques. Response to treatment (XRT+IdUrd+ """"""""modulating"""""""" drugs) will be assessed using growth delay (or tumor cure) in subcutaneous tumor implants and using survival time in mice with liver metastases or primary bladder tumors.
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