Inhibition of 5'-deoxy-5-fluorouridine phosphorolysis by acyclothymidine in tumor cell homogenates.
The inhibitory effect of acyclothymidine[AcyT, 5-methyl-1-(2'-hydroxyethoxymethyl) uracil], a potent pyrimidine nucleoside phosphorylase (PyNPase) inhibitor, on 5'-deoxy-5-fluorouridine (5'-DFUR) phosphorolysis in human and mouse tumor cell homogenates was measured. Competitive inhibition was observed in MKN-74 and Lewis lung carcinoma (LLC), whereas non-competitive inhibition was observed in HeLa. The strength of the inhibitory effect by AcyT showed the following pattern: HeLa < human normal intestine < mouse normal intestine < Colon 26 < LLC < MKN-74 < DLD-1. From the kinetic parameter obtained, we simulated the inhibitory effect of AcyT on 5'-DFUR phosphorolysis in tumor cells and the intestine. These data indicated that AcyT was more sensitive in normal mouse intestine than in Colon 26 and LLC, and that orally administered AcyT can reduce the intestinal toxicity of 5'-DFUR without reducing the antitumor effect in the mouse. The present finding may have an important implication for attempts to introduce AcyT, a potent PyNPase inhibitor, into the clinic.
Hamada
A
A
Department of Pharmacy, Kumamoto University Hospital, Japan.
Nakano
M
M
Shimidzu
S
S
Hasegawa
T
T
Kawaguchi
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005467:Floxuridine / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005467:Floxuridine; D014498:Uracil; C046151:N-(2-(hydroxyethoxy)methyl)-5-methyluracil; D013939:Thymidine Phosphorylase; C025034:doxifluridine