Cancer research
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Brequinar sodium is a quinoline carboxylic acid derivative that has shown antitumor activity in a number of in vivo murine and human tumor xenograft models. Its mechanism of action is blockade of de novo pyrimidine biosynthesis by inhibition of dihydroorotic acid dehydrogenase. In vitro and in vivo studies demonstrate the superiority of prolonged drug exposure in achieving tumor growth inhibition. ⋯ Analysis of the day 5 drug clearance curves revealed a diminution in Vmax to 30 (micrograms/ml)/h. As a consequence of the reduction in Vmax brequinar plasma concentrations on day 5 were higher than predicted from day 1 drug kinetics. Pharmacodynamic analysis of the day 1 kinetic parameters and the toxicities occurring during the first cycle of drug therapy revealed significant correlations between mucositis and dose, AUC, and peak brequinar concentration; between leukopenia and AUC and peak drug concentration; and between thrombocytopenia and beta elimination rate.
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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). ⋯ At dose levels of greater than or equal to 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.