Content area
Abstract
5-Fluoro-2$\sp\prime$-deoxyuridine (FdUrd), a pyrimidine nucleoside of 5-fluorouracil (FUra), is utilized primarily in the management of hepatic metastases of advanced gastrointestinal adenocarcinoma and, more recently, in the treatment of renal cell carcinoma. Much attention has been focused on the biochemistry and dose-limiting toxicity (i.e., hematological and gastrointestinal toxicity) of this drug. However, our knowledge of its degradation is incomplete despite the obvious importance of catabolism in limiting its availability. The primary objective of this dissertation project is to improve our understanding of the biochemical factors that determine host toxicity and antitumor activity with a major emphasis on the role of pyrimidine catabolism in fluoropyrimidine chemotherapy.
The activities of thymidine phosphorylase (dThdPase), the enzyme responsible for the phosphorolysis of FdUrd to FUra, and dihydropyrimidine dehydrogenase (DPD), the subsequent catabolic enzyme responsible for inactivating FUra to dihydrofluorouracil, were measured over a 24-hr period in rat liver. Utilizing cosinor analysis, no evidence of a circadian variation of dThdPase activity could be detected in rat liver homogenates. This enzyme also lacked a circadian pattern in human peripheral blood mononuclear cells. In contrast, DPD activity had a circadian pattern in rat liver homogenates. The peak of DPD activity was at approximately 10 hr after light onset (HALO), and the trough at approximately 22 HALO. These studies also suggested that DPD may be an important factor in the regulation of FdUrd degradation due to its low activity relative to the activity of dThdPase.
Since the liver is believed to be the primary site of pyrimidine catabolism and the intrahepatic infusion of FdUrd has been shown to be an effective means of drug delivery, the modulation of DPD activity in this organ was investigated. Utilizing the isolated perfused rat liver as a model, 5 benzyloxybenzyluracil (BBU) maximally inhibited FUra catabolism by approximately 83%, while FdUrd phosphorolysis was not affected. Inhibition of FUra catabolism allows an increased accumulation of intracellular FUra. An increase in the intracellular concentration of FUra may inhibit the phosphorolysis of FdUrd. Further studies examined the intracellular and extracellular concentration of FUra and its metabolites in parenchymal liver cells in the presence or absence of BBU. These studies confirmed that BBU inhibits FUra catabolism and not its transport into the cell.
