DEVELOPMENT OF IPDR AS A RADIOSENSITIZING DRUG

Sparta Pharmaceuticals, Inc., San Ramon CA

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Abstract

The pyrimidone nucleoside 5-iodo2'-pyrimidone-2'deoxyribose (IPdR) was initially developed as a anti-viral agent since it was thought it would be a substrate for viral but not mammalian thymidine kinase. Subsequent studies have demonstrated that IPdR can be converted to IUdR by aldehyde oxidase present mainly in the liver. IUdR has been recognized as an effective in vitro and in vivo radiosensitizer of human tumors for several decades. Phase I/II clinical studies suggest that it can radiosensitize poorly responsive (resistant) human tumors. We have shown in two recent studies that orally administered IPdR offers a greater therapeutic index for tumor incorporation, lower systemic toxicity and a calculated radiosensitization enhancement ratio of > 1.5 using human tumor xenografts, which would indicate the potential generation of clinically relevant radiosensitization of resistant tumors. Sparta intends to develop IPdR as an oral radiosensitizer for use in the treatment of CNS and other radioresistant cancers. In order to determine the feasibility of this development project, it is essential for us to determine: l) the extent of thymidine substitution in normal proliferating tissues (as an indicator of radiosensitization specificity); 2) IPdR's toxicity profile; and 3) the pharmacokinetics of IPdR and its metabolites which result from long term daily oral administration to animals. PROPOSED COMMERCIAL APPLICATIONS: Increasing laboratory and clinical evidence suggests that proliferation of many common human solid tumors is rapid and that tumor cell proliferation during radiation therapy may be responsible, in part, for the low response (cure) of some tumors. A clinical strategy to improve locoregional tumor control and cure rates in rapidly proliferating human tumors is to use a S-phase specific radiosensitizer. IPdR, having the potential to be such an agent, has great commercial potential to improve the therapeutic outcome of many cancers.