Abstract
DUP-785 (Brequinar sodium) is a novel potent inhibitor of the pyrimidine de novo enzyme dihydroorotic acid dehydrogenase (DHO-DH). We studied the relationship between DHO-DH activity and in vitro growth-inhibitory effects and in vivo antitumor effects of DUP-785. Seven cell lines from different histological origin were continuously exposed to DUP-785 for 48 hr. The human squamous carcinoma cell line 14C was most sensitive (IC50 0.19 μM), three other cell lines had a comparable IC50 of about 0.4 μM, while rat hepatoma H35 and murine leukemia L1210 had a IC50 of 2.6 and 5.9 μM, resp. DHO-DH activity varied between 15 and 20 μmol/hr.106 cells in the cell lines tested. Inhibition by 1.3 μM DUP-785 was 80-90% in the most sensitive lines, compared to 50% in H35 and 30% in L1210. The sensitivity of two murine colon tumors was investigated in vivo by injection of 50 mg/kg at day 0, 4, 8 and 12. The doubling time of Colon 26 for untreated and treated tumors was 2.7 and 2.8 days, resp, while for Colon 38 these values were 5.1 and 8.3 days, resp. DHO-DH activity was 230 and 167 nmol/hr per mg protein, resp. In both tumors 50 mg DUP-785/kg decreased DHO-DH activity to below 10% after 4 hr, which was partly recovered after 1 day. After 1 day the concentration of uridine nucleotides in Colon 26 decreased by 30% and in Colon 38 by 50%, followed by an increase of 130 and 180%, resp, after 4 days. In conclusion; in vitro the extent of inhibition of DUP-785 was related to the growth-inhibition, but in vivo this relation was less evident.
Article PDF
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Peters, G., Laurensse, E., De Kant, E. et al. 113 THE RELATIONSHIP BETWEEN DIHYDROOROTIC ACID DEHYDROGENASE AND IN VITRO AND IN VIVO CYTOSTATIC EFFECTS OF BREQUINAR (DUF-785; NSC 368390). Pediatr Res 24, 130 (1988). https://doi.org/10.1203/00006450-198807000-00137
Issue Date:
DOI: https://doi.org/10.1203/00006450-198807000-00137