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Cited by 27Biochemical and Molecular ResearchCancer therapeutics and mechanismsSynthesis and Characterization of Heterocyclic Compounds

Retention of in vivo antipyrimidine effects of Brequinar sodium (DUP-785; NSC 368390) in murine liver, bone marrow and colon cancer

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Peters, G.J., Nadal, J.C., Laurensse, E.J., de Kant, E., Pinedo, H.M.·1990·Biochemical Pharmacology
DOI 10.1016/0006-2952(90)90657-7
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Abstract

Brequinar sodium (DUP-785) is a potent inhibitor of the pyrimidine de novo enzyme, dihydroorotic acid dehydrogenase (DHO-DH). In order to determine whether in vitro data could be extrapolated to the in vivo situation we investigated antipyrimidine effects of DUP-785 in mice bearing colon cancer. Two tumor models were used, Colon 26 and Colon 38, resistant and moderately sensitive to DUP-785, respectively. DUP-785 at 50 mg/kg caused a depletion of plasma uridine in mice, and depleted tissue uridine levels in Colon 38 down to 10%, which was retained for several days; in Colon 26 the decrease was less and tissue uridine levels recovered rapidly. In livers of these mice no significant effect on uridine was observed. DUP-785 depleted UTP in bone marrow cells within 2 hr to 25% of control levels, after 4 days normal levels were found. In livers of both Balb-c mice (bearing Colon 26) and C57Bl/6 mice (bearing Colon 38) a small decrease of uridine nucleotide pools was found. In Colon 26 DUP-785 increased uridine nucleotide pools to 170% after 2 hr, at 1 day normal levels were observed, but after 2 days again an increase was found. In Colon 38 DUP-785 decreased the uridine nucleotide pool by 50% after 1 and 2 days. DUP-785 did not affect cytidine nucleotide pools of livers and of Colon 26 and Colon 38. The ratio between uridine nucleotides and cytidine nucleotides decreased from 2.2 to 0.90 in Colon 38, in the other tissues the decrease was less. DHO-DH was measured in bone marrow cells and Colon 26 and 38 before and after treatment. Basal levels of DHO-DH were 3 times higher in Colon 26 than in Colon 38. In treated tumors DHO-DH was initially inhibited by more than 90%, after 7 days enzyme activity in Colon 26 was 50% and in Colon 38 about 200% of basal levels. In bone marrow cells DHO-DH was also rapidly inhibited but recovered within 4 days. It is concluded that the retention of antipyrimidine effects of DUP-785 in Colon 38 were more pronounced than in Colon 26, which is in agreement with the better antitumor effect of DUP-785 in Colon 38.

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  • Brequinar sodium was previously evaluated to treat advanced solid tumors but was not shown to be effective in clinical trials.

    “BRQ was previously evaluated to treat advanced solid tumors but was not shown to be effective in clinical trials (Arteaga et al., 1989; Noe et al., 1990; Peters et al., 1990).”

    From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Peters et al., 1990

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Authors
Peters, G. J., Nadal, J. C., Laurensse, E. J., de Kant, E., & Pinedo, H. M.
Affiliations
Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
Corresponding author
Peters, G.J.
ORCID
Venue
Biochemical Pharmacology
Publisher
Elsevier BV
Published
1990-01
Volume
39
Issue
1
Pages
135-144
ISSN
0006-2952 (ISSN-L)
DOI
10.1016/0006-2952(90)90657-7
OpenAlex
W2027440636
Cited by
27
References
37
Citations by year
2025: 1 · 2021: 1 · 2018: 2 · 2017: 2 · 2015: 1 · 2013: 1
FWCI
1.57
Type
journal article
Language
en
Open access
Licence
Locations
  • Biochemical Pharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion, other-oa)
  • Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
  • Physical Sciences › Chemistry › Organic Chemistry › Synthesis and Characterization of Heterocyclic Compounds
Keywords
brequinar sodium, uridine nucleotides, tumor xenografts, colon cancer, bone marrow, liver, drug resistance, nucleotide pools, cytidine nucleotides
MeSH terms
Animals, Antineoplastic Agents, Biphenyl Compounds, Bone Marrow, Colonic Neoplasms, Dihydroorotate Oxidase, Female, Liver, Mice, Inbred BALB C, Mice, Inbred C57BL, Oxidoreductases, Pyrimidine Nucleotides, Quinaldines, Uridine, Uridine Triphosphate, Mice

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