Regulation of dihydropyrimidine dehydrogenase and pyrimidine nucleoside phosphorylase activities by growth factors and subsequent effects on 5-fluorouracil sensitivity in tumor cells.
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)-alpha on cell growth and tumoral DPD and PyNPase activities, and the subsequent effects on 5-FU sensitivity in uterine cervical carcinoma SKG-IIIb cells. The treatment of tumor cells with EGF or TGF-alpha resulted in a concentration-dependent increase in tumor cell growth and PyNPase activity, whereas tumoral DPD activity was inhibited. Their stimulatory effects on tumor cell growth correlated well with PyNPase activity, but were inversely related to DPD activity (P < 0.01). 5-FU sensitivity of tumor cells increased in the presence of EGF or TGF-alpha. These growth factors were shown to stimulate the first, rate-limiting enzyme activity in 5-FU anabolism and to inhibit that in 5-FU catabolism, leading to enhancement of the antiproliferative action of 5-FU at achievable therapeutic levels. The tumor environmental factors, EGF and TGF-alpha, may act as intrinsic regulators of DPD and PyNPase activities that affect the 5-FU sensitivity of individual tumors.
Ueda
M
M
Department of Obstetrics and Gynecology, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan. gyn017@poh.osaka-med.ac.jp
Kitaura
K
K
Kusada
O
O
Mochizuki
Y
Y
Yamada
N
N
Terai
Y
Y
Kumagai
K
K
Ueki
K
K
Ueki
M
M
D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D042943:Dihydrouracil Dehydrogenase (NADP); D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005260:Female; D005472:Fluorouracil / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010430:Pentosyltransferases / Q000378:metabolism*; D057845:Pyrimidine Phosphorylases; D016211:Transforming Growth Factor alpha / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology
D000964:Antimetabolites, Antineoplastic; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D010430:Pentosyltransferases; D057845:Pyrimidine Phosphorylases; D005472:Fluorouracil