Combination of the chemotherapeutic agent 5-fluorouracil with an inhibitor of its catabolism results in increased micronucleus induction.
The rate limiting step in 5-fluorouracil catabolism is catalyzed by the enzyme dihydropyrimidine dehydrogenase. Since degradation of 5-fluorouracil decreases its efficacy in chemotherapy, the inhibition of its catabolism is a promising tool. We investigated the formation of micronuclei in vitro in mouse L5178Y cells. 5-fluorouracil induced an increase in micronucleus frequency, which could significantly be enhanced by the concurrent application of 2,6-dihydroxypyridine, an inhibitor of dihydropyrimidine dehydrogenase. The 5-fluorouracil concentration necessary to reach maximal genotoxic effects could be reduced to half in the presence of inhibitor 2,6-Dihydroxypyridine alone and the naturally occurring enzyme substrate uracil did not induce micronucleus formation. Combined application of the chemotherapeutic agent 5-fluorouracil and an inhibitor of its could reduce side-effects by lowering the effective dose of the active drug. With this study we provide further support for the usefulness of this concept.
Stopper
H
H
Institute of Pharmacology and Toxicology, University of Würzburg, Germany.
Kühnel
A
A
Podschun
B
B
D000818:Animals; D001665:Binding Sites; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil / Q000494:pharmacology*; D007700:Kinetics; D007739:L Cells / Q000187:drug effects / Q000648:ultrastructure*; D008099:Liver / Q000201:enzymology; D051379:Mice; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects / Q000648:ultrastructure*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D013552:Swine; D014498:Uracil / Q000378:metabolism / Q000494:pharmacology
D011725:Pyridines; D014498:Uracil; C089431:2,6-dihydroxypyridine; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil