Dihydropyrimidine dehydrogenase (DPD) and pyrimidine nucleoside phosphorylase (PyNPase) are the first and rate-limiting enzymes that regulate 5-fluorouracil (5-FU) metabolism, and tumoral DPD activity appears to be a promising predictor of 5-FU sensitivity. However, the regulatory mechanisms determining these enzyme activities have not been fully understood. We investigated the biological effects of epidermal growth factor (EGF) and transforming growth factor (TGF)-α α α α Key words: Dihydropyrimidine dehydrogenase -Pyrimidine nucleoside phosphorylase -Growth factor -5-Fluorouracil sensitivity -Cervical cancer 5-Fluorouracil (5-FU) has been widely used in the treatment of a variety of neoplastic diseases, particularly cancers of the breast and digestive organs, and is given either alone or in combination with other cytostatics. We have demonstrated that 5-FU-based chemotherapy is also useful for the treatment of uterine cervical cancer.1, 2) Two main modes of action have been proposed for 5-FU through its active metabolites, 5-fluoro-dUMP (FdUMP) and 5-fluoro-UTP. FdUMP suppresses thymidylate synthetase (TS) by forming a covalent ternary complex with 5,10-methylenetetrahydrofolate, which inhibits DNA synthesis.3) 5-Fluoro-UTP is incorporated into cellular RNA, resulting in RNA dysfunction. 4) 5-FU is initially anabolized by pyrimidine nucleoside phosphorylase (PyNPase) in both pathways. Thymidine phosphorylase (ThdPase) converts 5-FU to 5-fluorodeoxyuridine (FUdR), a precursor of FdUMP. Uridine phosphorylase (UrdPase) converts 5-FU to 5-fluorouridine (FUR), a precursor of 5-fluoro-UMP, which is finally metabolized to 5-fluoro-UTP. The former enzyme is identical to platelet-derived endothelial cell growth factor (PD-ECGF) 5) and is closely associated with tumor angiogenesis.5, 6) 5-FU is initially catabolized to 5-fluorodihydrouracil (DHFU) by dihydropyrimidine dehydrogenase (DPD), mainly in the liver, then dihydropyrimidinase and β-ureido-propionase catalyze the formation of 2-fluoro-β-alanine. Several recent studies 7-10) concerned with 5-FU antitumor effects have demonstrated that tumoral DPD activity may influence 5-FU sensitivity. Thus, DPD and PyNPase are considered to be the first and rate-limiting enzymes in the chain of reactions that regulate 5-FU metabolism.Determination of tumoral DPD has become of clinical interest because elevated intratumoral DPD can influence the tumor response to 5-FU therapy as a result of increased inactivation. Etienne et al. 8) evaluated DPD activity in tumor biopsy specimens from head and neck cancer patients before administration of 5-FU and found that the tumoral/non-tumoral DPD activity ratio was higher in the non-responding patients than in those with a partial or complete response. Moreover, certain biochemical modulations to enhance the antitumor activity of 5-FU by inhibiting intratumoral DPD activity have been attempted. 11,12) The underlying differences in tumoral DPD activity result in a variable 5-FU degradation prior to 5-FU
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