3-Cyano-2,6-dihydroxypyridine (CNDP), a new potent inhibitor of dihydrouracil dehydrogenase.

doi:10.1093/OXFORDJOURNALS.JBCHEM.A124276

Paper

3-Cyano-2,6-dihydroxypyridine (CNDP), a new potent inhibitor of dihydrouracil dehydrogenase.

Published Dec 1, 1993 · K. Tatsumi, T. Yamauchi, K. Kiyono

Journal of biochemistry

Q2 SJR score

22

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0

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Abstract

3-Cyano-2,6-dihydroxypyridine (CNDP) was identified as a potent inhibitor (IC50 value, 4.4 nM) of dihydrouracil dehydrogenase (DHUDase) [EC 1.3.1.2], a rate-limiting enzyme in 5-fluorouracil (5-FU) degradation. The inhibitory activity of CNDP was about 2,000 times that of uracil under our assay conditions. Kinetic analyses with partially purified enzyme from rat liver revealed that the mechanism of inhibition of DHUDase by CNDP was of mixed type with an inhibition constant (Ki) of 1.51 nM. CNDP had less effect on 5-FU phosphorylation than on 5-FU degradation. The inhibitory effect of CNDP on ribosylation of 5-FU was 600 to 1,000 times less than that on DHUDase. Moreover, CNDP did not inhibit uridine kinase, thymidine kinase, or pyrimidine phosphoribosyltransferase. Coadministration of CNDP with 1-ethoxymethyl-5-fluorouracil (EM-FU) to rats with Yoshida sarcoma elevated the level of 5-FU in both the blood and the tumor and enhanced the antitumor effect of EM-FU. These findings indicated that CNDP would be a useful chemical modulator in chemotherapy with 5-FU or its prodrugs.

In Vitro Study

Study Snapshot

CNDP is a potent inhibitor of dihydrouracil dehydrogenase, which could enhance the antitumor effect of 5-fluorouracil chemotherapy in cancer treatment.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

3-Cyano-2,6-dihydroxypyridine (CNDP), a new potent inhibitor of dihydrouracil dehydrogenase.

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References

Citations

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Drug delivery of oral anti-cancer fluoropyrimidine agents

Oral 5-FU prodrugs can replace intravenous 5-FU in many cancer chemotherapy regimens, and their efficacy can be further improved by combining them with DPD inhibitors and biochemical modulators.

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