This revised (A1) competitive grant renewal requests support for an additional 3-year period to continue in vitro and in vivo laboratory investigations in radioresistant human tumor cell lines and correlative pre-clinical testing in human and mouse normal tissues using new approaches to human tumor radiosensitization with the halogenated thymidine (dThd) analogs (BrdUrd; IdUrd) and related pyrimidinone compounds. Based on information generated in the present grant, we propose to investigate 3 specific aims in this grant renewal to further improve the therapeutic gain of human tumor radiosensitization. First, our in vitro and in vivo studies suggest that the concomitant use of direct (5'-amino-5'deoxythymidine, 5'-AdThd) or indirect (hydroxyurea, HU) modulators of TK activity with the dThd analogs can selectively enhance tumor radiosensitization without significantly increased normal tissue toxicities. We propose to further characterize the cellular and biochemical interactions of these TK modulators and the halogenated dThd analogs to enhance tumor radiosensitization under Specific Aim #1. Second, we will test the hypothesis that differences in the (de)regulation of TK in human tumors compared to normal tissues and in differential TK induction following I can be exploited to selectively increase drug (BrdUrd, IdUrd) activation, DNA incorporation and subsequent radiosensitization in radioresistant tumors in vitro and in vivo (Specific Aim #2). Finally, under Specific Aim #3, we propos to continue pre-clinical testing of 5-iodo-2-pyrimidinone-2'deoxyribose (EPdR) as an orally (p.o.) bioavailable prodrug for IdUrd-mediated radiosensitization We have shown in athymic nude mice with human tumor xenografts that p.o. IPdR is rapidly absorbed and undergoes efficient conversion to IdUrd, principally b hepatic aldehyde oxidase, resulting in high plasma IdUrd levels for up to 2-3 hrs following a p.o. bolus. Compared to a 6-day course of p.o. bolus or continuous infusion IdUrd at the maximum tolerated dose, IPdR (p.o. QD x 6) resulted in an improved therapeutic gain as evidenced by both an increase in tumor cell % DNA incorporation and a decrease in % DNA incorporated in proliferating normal tissues.
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