IMPROVING 5-FU WITH A NOVEL DIHYDROPYRIMIDINE DEHYDROGENASE INACTIVATOR

GW776C85 is a new drug that has been shown to be an effective inactiva tor of dihydropyrimidine dehydrogenase (DPD). Preclinical studies demo nstrated that administration of GW776C85 with 5-fluorouracil (5-FU) re sulted in several desirable pharmacologic effects. Initial clinical da ta on 5-FU combined with GW776C85 suggest potentially increased antitu mor. activity in at least some malignancies with tolerable toxicity, a s well as several distinct economic and quality-of-life advantages inc luding the following: (I) The possibility of administering 5-FU as an oral drug due to excellent bioavailability of 5-FU following inactivat ion of DPD; (2) a cost-effective alternative to continuous or protract ed infusion of 5-FU without the need for hospitalization or surgical p lacement of an intravenous access and availability of an ambulatory pu mp; and (3) potential for less interpatient variation of 5-FU toxicity (eg, in host tissues, such as bone marrow and gastrointestinal mucosa cells) due to inactivation-of DPD in essentially all patients treated , permitting better 5-FU dosing guidelines. Finally, because tumors ma y theoretically become resistant to 5-FU by increased levels of DPD, t he use of GW776C85 to inactivate DPD may provide a potential means by which tumor. resistance can be reversed.