In vitro and in vivo studies on the combination of brequinar sodium (dup-785; nsc 368390) with 5-fluorouracil; effects of uridine

ABSTRACT Brequinar sodium (DUP-785; Brequinar) is a potent inhibitor of the pyrimidine de novo enzyme dihydroorotate dehydrogenase (DHO-DH), leading to a depletion of pyrimidine nucleotides,

which could be reversed by uridine. In in vitro studies we investigated the effect of different physiological concentrations of uridine on the growth-inhibition by Brequinar, the effect of

the nucleoside transport inhibitor, dipyridamole, and the combination of Brequinar and 5-fluorouracil (5FU). Uridine at 1 microM slightly reversed the growth inhibition by Brequinar, while

the effect of 5-500 microM was greater. However, at Brequinar concentrations greater than 30 microM, uridine could not reverse the growth-inhibitory effects. Addition of dipyridamole could

only partially prevent the reversing effects of uridine. The combination of Brequinar and 5FU was more than additive in the absence of uridine in the culture medium, but not in the presence

of uridine. The combination of Brequinar and 5FU was tested in vivo in two murine colon tumour models, Colon 26 and Colon 38. Scheduling of both compounds appeared to be very important. In

Colon 38 no potentiating effect of Brequinar could be observed. In contrast in Colon 26 a more than additive effect could be observed. Since uridine concentrations are considerably different

in these tumours (higher in Colon 38), it was concluded from both the in vitro and in vivo experiments that uridine is an important determinant in combinations of Brequinar and 5FU. Access

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SIMILAR CONTENT BEING VIEWED BY OTHERS PHARMACOLOGIC MODULATION OF 5-FLUOROURACIL BY FOLINIC ACID AND HIGH-DOSE PYRIDOXINE FOR TREATMENT OF PATIENTS WITH DIGESTIVE TRACT CARCINOMAS Article

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AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Oncology, Free University Hospital, Amsterdam, The Netherlands GJ Peters Authors * GJ Peters View author publications You can also

search for this author inPubMed Google Scholar * I Kraal View author publications You can also search for this author inPubMed Google Scholar * HM Pinedo View author publications You can

also search for this author inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Peters, G., Kraal, I. & Pinedo, H. _In vitro_ and

_in vivo_ studies on the combination of Brequinar sodium (DUP-785; NSC 368390) with 5-fluorouracil; effects of uridine. _Br J Cancer_ 65, 229–233 (1992). https://doi.org/10.1038/bjc.1992.46

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