Research Project
6550790
DESCRIPTION (provided by applicant): 5-Fluorouracil (FUra) is among the few "standard" drugs effective against solid tumors in man (e.g. colorectal, breast, and head and neck cancers). FUra is the only drug in the market that shows synergism with most other anti-cancer agents in combination therapy. However, the full chemotherapeutic potential of FUra has not yet been totally realized. Increasing the dose of FUra to improve its efficacy has been hampered by host-toxicity. Uridine has been shown to allow increasing FUra doses which resulted in better anticancer efficacy and without the host-toxicity associated with high doses of FUra. Nevertheless, because of its rapid degradation, large doses (10-12 g/m2) of uridine are required in such regimens, and such doses induce toxic side-effects. We have designed and synthesized PTAU (5-phenylthioacyclouridine) as a potent and specific inhibitor of uridine degradation. Our preliminary results indicate that PTAU is not toxic and is 100% orally bioavailable. Furthermore, oral PTAU significantly increased the bioavailable uridine to adequate levels for a period of time sufficient to protect from the toxicity of high doses of FUra required for better anticancer activity. The overall objective of this proposal is to expand our preliminary results and explore the feasibility of modulating and increasing the concentration and half life of plasma uridine by PTAU and (2) to determine the effects of this compound on the chemotherapeutic efficacy and host-toxicity of FUra in mice. The goal is to improve the therapeutic index of this important anticancer drug through enhancing its efficacy by administering higher doses, while preventing the host-toxicity associated with such high doses. Two patents [(US Patents 5,476,855 (1995) and 5,721,241 (l998)] have been awarded to protect the technology and were licensed to the Company. Because of the importance and large market for Fura chemotherapy, the clinical and financial impact of the technology are quite substantial. Should PTAU prove to be effective in these Phase 1 studies, we will propose in Phase 2 to perform the pharmacokinetic, efficacy and toxicology studies needed for an IND filing with FDA . PROPOSED COMMERCIAL APPLICATION: The commercial potential for the proposed combination therapy is considerable. The sales of FUra represents a substantial market. Currently FUra is one of the principal drugs used in the clinic for the treatment of solid cancers. However, its full chemotherapeutic potential has not yet been fully realized because of the toxic limitations of higher doses. The proposed technology is aimed at increasing the doses of FUra for better anticancer efficacy without causing host toxicity. This will increase the use of FUra and enhance its commercial potential. Two patents have been awarded to protect the technology and were licensed to the Company.
