Improving 5-FU With A Novel Dihydropyrimidine Dehydrogenase Inactivator

GW776C85 is a new drug that has been shown to be an effective inactivator of dihydropyrimidine dehydrogenase (DPD). Preclinical studies demonstrated that administration of GW776C85 with 5-fluorouracil (5-FU) resulted in several desirable pharmacologic effects. Initial clinical data on 5-FU combined with GW776C85 suggest potentially increased antitumor activity in at least some malignancies with tolerable toxicity, as well as several distinct economic and quality-of-life advantages including the following: (1) The possibility of administering 5-FU as an oral drug due to excellent bioavailability of 5-FU following inactivation of DPD; (2) a cost-effective alternative to continuous or protracted infusion of 5-FU without the need for hospitalization or surgical placement of an intravenous access and availability of an ambulatory pump; 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 may theoretically become resistant to 5-FU by increased levels of DPD, the use of GW776C85 to inactivate DPD may provide a potential means by which tumor resistance can be reversed. [ONCOLOGY(Suppl 4):51-56, 1998]

ABSTRACT: GW776C85 is a new drug that has been shown to be an effective inactivator of dihydropyrimidine dehydrogenase (DPD). Preclinical studies demonstrated that administration of GW776C85 with 5-fluorouracil (5-FU) resulted in several desirable pharmacologic effects. Initial clinical data on 5-FU combined with GW776C85 suggest potentially increased antitumor activity in at least some malignancies with tolerable toxicity, as well as several distinct economic and quality-of-life advantages including the following: (1) The possibility of administering 5-FU as an oral drug due to excellent bioavailability of 5-FU following inactivation of DPD; (2) a cost-effective alternative to continuous or protracted infusion of 5-FU without the need for hospitalization or surgical placement of an intravenous access and availability of an ambulatory pump; 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 may theoretically become resistant to 5-FU by increased levels of DPD, the use of GW776C85 to inactivate DPD may provide a potential means by which tumor resistance can be reversed. [ONCOLOGY(Suppl 4):51-56, 1998]

Dihydropyrimidine dehydrogenase (dihydrouracil dehydrogenase, dihydrothymine dehydrogenase, uracil reductase, EC 1.3.1.2, DPD) is the initial rate-limiting enzymatic step in the catabolism of not only the naturally occurring pyrimidines uracil and thymine, but also the widely used antimetabolite cancer chemotherapy agent 5-fluorouracil (5-FU).[1,2] DPD thus occupies an important position in the overall metabolism of 5-FU, converting over 85% of clinically administered 5-FU to 5-FUH₂, an inactive metabolite, in an enzymatic step that is essentially irreversible (Figure 1).[3] While anabolism is clearly critical in the conversion of 5-FU to the active nucleotides FdUMP, FUTP, and FdUTP (which, in turn, can inhibit cell replication through inhibition of thymidylate synthase, or through incorporation into RNA or DNA, respectively), catabolism controls the amount of 5-FU available for anabolism and thus occupies a critical position in the overall metabolism of 5-FU.

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