The overall aim of this revised 4 year competitive renewal grant (years 9-12) is to better understand the biochemical, cellular and pharmacological mechanisms of human tumor radiosensitization, using relevant in vivo experimental models, by the halogenated thymidine analog, iododeoxyuridine (IudR) and its prodrug. We also propose to design and implement two initial Phase I clinical trials to increase the therapeutic index for human tumor radiosensitization by the prodrug 5- iodo-2-pyrimidinone-2'-deoxyribose (IPdR). Two specific aims are proposed in this revised proposal. In Specific Aim 1, we propose to continue our in vivo studies of 5-iodo- 2-pyrimidinone-2'-deoxyribose (IPdR) as an oral (po) prodrug for IudR- mediated human tumor radiosensitization. The major hypothesis to be tested in Aim 1 is that more frequent (BID/TID) daily dosing for longer periods (up to 28 days) of po IPdR will further improve the therapeutic index for human tumor radiosensitization, based on our current understanding of IPdR metabolism, pharmacokinetics and systemic toxicities. We will also assess the efficacy of po IpdR as an in vivo radiosensitizer using mice bearing xenografts from genetically-matched human tumor and derived murine embryonic cell lines which differ in MMR status for the two principal MMR genes/proteins recognized in hereditary (HNPCC) and sporadic human cancers (MLH1 and MSH2). In Specific Aim 2, we propose to initiate the first two Phase I clinical and pharmacokinetic studies of IpdR as a radiosensitizing drug. We hypothesize that po IpdR in humans will result in higher (but transient) plasma IudR levels, higher levels of IudR-DNA incorporation in tumor, and less systemic toxicity to one marrow and the GI mucosa which should lead to an improved therapeutic gain and more effective tumor radiosensitization compared to our prior results with continuous infusion IudR.