In vivo inhibition of the pyrimidine de novo enzyme dihydroorotic acid dehydrogenase by brequinar sodium (DUP-785; NSC 368390) in mice and patients

G. J. Peters, G. Schwartsmann, J. C. Nadal, E. J. Laurensse, C. J. Van Groeningen, W. J F Van Der Vijgh, H. M. Pinedo

Research output: Contribution to journalArticle

Abstract

Little is known about the in vivo effects of inhibition of the mitochondrial pyrimidine de novo synthesis enzyme dihydroorotic acid dehydrogenase (DHO-DH). In mice a new inhibitor of DHO-DH, Brequinar sodium (DUP-785, NSC 368390) depleted the plasma uridine concentration to 40% within 2 h, followed by a small rebound after 7-9 days. The drug was subsequently evaluated in a Phase I clinical trial, during which it was possible to follow its biochemical effects in 24 patients (27 courses). In addition to the measurement of plasma uridine concentrations, we also measured in lymphocytes of 9 patients (10 courses) the duration of DHO-DH inhibition. Brequinar sodium was administered every 3 weeks as an i.v. infusion at dose levels of 15-2250 mg/m2. The biochemical effects were studied following the first administration of the drug. In sonicated extracts of lymphocytes from 7 healthy volunteers the activity of DHO-DH varied from 2.0 to 3.9 nmol/h per 106 cells, while in the lymphocytes of 9 patients obtained immediately before treatment this value was between 0.5 and 4.8 nmol/h per 106 cells. Within 15 min of drug administration DHO-DH activity was not detectable and was still low up to 1 week later. Duration of the inhibition appeared to be related to the extent of clinical toxicity, e.g., myelosuppression, nausea, vomiting, diarrhea, and mucositis. Severe lymphopenia was observed in patients receiving Brequinar sodium at the maximum tolerated dose. At dose levels of ≥600 mg/m2, uridine depletion (40-85%) was observed between 6 h and 4 days, followed by a rebound of 160-350% after 4-7 days. The extent of the depletion and of the accompanying rebound of uridine levels and the extent and duration of DHO-DH inhibition in the individual patients could be partially associated with drug toxicity in these patients. This is the first report describing biological effects of DHO-DH inhibition in humans in relation to the degree and duration of inhibition of this enzyme.

Original languageEnglish (US)
Pages (from-to)4644-4649
Number of pages6
JournalCancer Research
Volume50
Issue number15
StatePublished - Aug 1 1990
Externally publishedYes

Fingerprint

brequinar
Oxidoreductases
Uridine
Acids
Enzymes
Lymphocytes
Pharmaceutical Preparations
Clinical Trials, Phase I
Mucositis
Lymphopenia
Maximum Tolerated Dose
pyrimidine
Drug-Related Side Effects and Adverse Reactions
Nausea
Vomiting
Diarrhea
Healthy Volunteers

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Peters, G. J., Schwartsmann, G., Nadal, J. C., Laurensse, E. J., Van Groeningen, C. J., Van Der Vijgh, W. J. F., & Pinedo, H. M. (1990). In vivo inhibition of the pyrimidine de novo enzyme dihydroorotic acid dehydrogenase by brequinar sodium (DUP-785; NSC 368390) in mice and patients. Cancer Research, 50(15), 4644-4649.

In vivo inhibition of the pyrimidine de novo enzyme dihydroorotic acid dehydrogenase by brequinar sodium (DUP-785; NSC 368390) in mice and patients. / Peters, G. J.; Schwartsmann, G.; Nadal, J. C.; Laurensse, E. J.; Van Groeningen, C. J.; Van Der Vijgh, W. J F; Pinedo, H. M.

In: Cancer Research, Vol. 50, No. 15, 01.08.1990, p. 4644-4649.

Research output: Contribution to journalArticle

Peters, GJ, Schwartsmann, G, Nadal, JC, Laurensse, EJ, Van Groeningen, CJ, Van Der Vijgh, WJF & Pinedo, HM 1990, 'In vivo inhibition of the pyrimidine de novo enzyme dihydroorotic acid dehydrogenase by brequinar sodium (DUP-785; NSC 368390) in mice and patients', Cancer Research, vol. 50, no. 15, pp. 4644-4649.
Peters GJ, Schwartsmann G, Nadal JC, Laurensse EJ, Van Groeningen CJ, Van Der Vijgh WJF et al. In vivo inhibition of the pyrimidine de novo enzyme dihydroorotic acid dehydrogenase by brequinar sodium (DUP-785; NSC 368390) in mice and patients. Cancer Research. 1990 Aug 1;50(15):4644-4649.
Peters, G. J. ; Schwartsmann, G. ; Nadal, J. C. ; Laurensse, E. J. ; Van Groeningen, C. J. ; Van Der Vijgh, W. J F ; Pinedo, H. M. / In vivo inhibition of the pyrimidine de novo enzyme dihydroorotic acid dehydrogenase by brequinar sodium (DUP-785; NSC 368390) in mice and patients. In: Cancer Research. 1990 ; Vol. 50, No. 15. pp. 4644-4649.
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abstract = "Little is known about the in vivo effects of inhibition of the mitochondrial pyrimidine de novo synthesis enzyme dihydroorotic acid dehydrogenase (DHO-DH). In mice a new inhibitor of DHO-DH, Brequinar sodium (DUP-785, NSC 368390) depleted the plasma uridine concentration to 40{\%} within 2 h, followed by a small rebound after 7-9 days. The drug was subsequently evaluated in a Phase I clinical trial, during which it was possible to follow its biochemical effects in 24 patients (27 courses). In addition to the measurement of plasma uridine concentrations, we also measured in lymphocytes of 9 patients (10 courses) the duration of DHO-DH inhibition. Brequinar sodium was administered every 3 weeks as an i.v. infusion at dose levels of 15-2250 mg/m2. The biochemical effects were studied following the first administration of the drug. In sonicated extracts of lymphocytes from 7 healthy volunteers the activity of DHO-DH varied from 2.0 to 3.9 nmol/h per 106 cells, while in the lymphocytes of 9 patients obtained immediately before treatment this value was between 0.5 and 4.8 nmol/h per 106 cells. Within 15 min of drug administration DHO-DH activity was not detectable and was still low up to 1 week later. Duration of the inhibition appeared to be related to the extent of clinical toxicity, e.g., myelosuppression, nausea, vomiting, diarrhea, and mucositis. Severe lymphopenia was observed in patients receiving Brequinar sodium at the maximum tolerated dose. At dose levels of ≥600 mg/m2, uridine depletion (40-85{\%}) was observed between 6 h and 4 days, followed by a rebound of 160-350{\%} after 4-7 days. The extent of the depletion and of the accompanying rebound of uridine levels and the extent and duration of DHO-DH inhibition in the individual patients could be partially associated with drug toxicity in these patients. This is the first report describing biological effects of DHO-DH inhibition in humans in relation to the degree and duration of inhibition of this enzyme.",
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