Concurrent allopurinol and 5-fluorouracil: 5-fluoro-2'-deoxyuridylate formation and thymidylate synthase inhibition in rat colon carcinoma and in regenerating rat liver.
The formation of FdUMP and the inhibition of TS were studied in a subcutaneously growing transplantable rat colon carcinoma and in regenerating rat liver following bolus administration of 5-FU, with or without HPP pretreatment. In tumor, peak levels of FdUMP at 30 min following bolus 5-FU, 100 mg/kg, averaged 4931 +/- 587 pmol/g. Pretreatment with HPP, 50 mg/kg, 24 h and 1 h before 5-FU, reduced the peak FdUMP level to 2085 +/- 387 pmol/g. The inhibition of TS by 5-FU treatment was greater than 95% by 30 min, and after 48 h residual enzyme inhibition averaged 40%. No effect on TS inhibition by 5-FU treatment could be observed as a result of HPP pretreatment. The levels of TStot increased linearly after 5-FU treatment and doubled within 48 h. In regenerating rat liver, neither FdUMP levels nor TS inhibition, studied at 1 h after bolus 5-FU, were affected by HPP pretreatment.
Berne
M
M
Department of Surgery, Ostra Sjukhuset, University of Gothenburg, Sweden.
Gustavsson
B
B
Almersjö
O
O
Spears
C P
CP
Waldenström
J
J
D000230:Adenocarcinoma / Q000201:enzymology / Q000378:metabolism*; D000493:Allopurinol / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D003110:Colonic Neoplasms / Q000201:enzymology / Q000378:metabolism*; D003856:Deoxyuracil Nucleotides / Q000096:biosynthesis*; D005260:Female; D005468:Fluorodeoxyuridylate / Q000096:biosynthesis* / Q000493:pharmacokinetics; D005472:Fluorouracil / Q000008:administration & dosage* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D013997:Time Factors
D003856:Deoxyuracil Nucleotides; D005468:Fluorodeoxyuridylate; D000493:Allopurinol; D013940:Thymidylate Synthase; D005472:Fluorouracil