Increasing laboratory and clinically evidence suggests that proliferation of many common solid tumors is rapid and that tumor cell proliferation during treatment may decrease local control and survival. A clinical strategy to improve tumor response in rapidly proliferating human tumors is use S-phase specific radio- and chemosensitizers such as the halogenated pyrimidine analogs (IUdR, BudR, BudR, FudR, FU) and pyrimidinone analogs (IPdR, FRdR). These drugs are taken up and metabolized only by cells synthesizing DNA so that increased tumor proliferation should result in increased radiosensitization and chemosensitization. However, S-phase specific drug uptake by adjacent and/or dose-limiting normal tissue could limit the therapeutic gain. Nevertheless, there are an increasing number of recent positive clinical trials in several different common tumors using these S-phase sensitizers, suggesting clinical sensitization was achieved although usually with increased local and systemic toxicities. In spite of these impressive clinical data, the basic mechanisms of these drug-radiation and drug-drug interactions are poorly understood. Our experimental data suggest that the thymidine analogs (IUdR,BUdR) can significantly increase initial radiation damage while the uridine analogs (FU,FUdR) can alter cell kinetics and deoxynucleotides pools with consequent effects on radiation damage. Thus, while 2 groups of halogenated pyrimidine share similar metabolic pathways, the cellular and molecular mechanisms of radiosensitization and probably chemosensitization appear different. We propose to further investigate both groups of pyrimidine analogs in two relevant human tumor systems both in vitro and in vivo with the goal of maximizing the therapeutic gain in future clinical trials. The pyrimidinone analogs will also be studied in vivo. The overall objectives of these studies continue to be: 1) The examination of cellular and molecular mechanisms of radio-and chemosensitization by the halopyrimidines and related compounds in human colorectal and bladder cancer cells; 2) The examination of biochemical modulation of the key enzymes of thymidine metabolism [including thymidine kinase (TK) and thymidylate synthase (TS)] to enhance radio- and/or chemosensitization by S-phase sensitizers in human colorectal and bladder cancer cells; and 3) The examination of alterations in vitro/in vivo cell kinetics and drug uptake tumor and dose-limiting normal tissues to enhance the therapeutic gain following various treatment schedules with halopyrimidines and related compounds. Close biostatistical collaboration is necessary to realize these objectives.
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