Disease relevance of Biphenquinate

• 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 [1].
• Cisplatin/brequinar doses of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2, were associated with dose limiting toxicity in 0/3, 1/3, 1/3, 1/3, 2/4, 2/5, and 4/6 patients, respectively [2].
• We conclude that, at this dose and schedule, brequinar has no activity in advanced melanoma [3].
• We conclude that brequinar given at this dose and on this schedule has no significant activity in advanced squamous-cell carcinoma of the head and neck [4].
• One patient developed grade 3 stomatitis, and one developed grade 3 esophagitis at the 400 and 600 mg/m2 dose of brequinar, respectively [5].

High impact information on Biphenquinate

• This effect was achieved with very low nontherapeutic doses of Brequinar (8 to 27% of the maximum tolerated dose in this model) [6].
• 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 [1].
• Brequinar exhibits a high level of bioavailability following oral administration and an extended half-life that permits less frequent administration [7].
• Multiple inhibitor analysis of the brequinar and leflunomide binding sites on human dihydroorotate dehydrogenase [8].
• In the present experiments, a multimodality regimen was developed that included an anti-T cell receptor R73 monoclonal antibody and the pharmacologic agents brequinar (BQR), cyclosporine (CsA), and sirolimus (rapamycin; RAPA) to prolong the survival of small bowel (SB) allografts [9].

Chemical compound and disease context of Biphenquinate

• We conclude that a potential synergism in immunosuppression using combinations of brequinar (analogues) and cyclosporine can be complicated by enhanced toxicity of the compounds [10].
• Effects of brequinar and ciprofloxacin on de novo nucleotide biosynthesis in mouse L1210 leukemia [11].

Biological context of Biphenquinate

• The maximally tolerated dose of Brequinar on a daily x 5 i.v. schedule was 250 mg/m2 for good risk patients [12].
• The dose versus AUC relationship was well described using a Michaelis-Menten model of brequinar elimination kinetics with Vmax = 45 (micrograms/ml)/h and Km = 123 micrograms [1].
• Effects of plasma protein binding displacement on the pharmacokinetics, tissue and tumor concentrations and efficacy of brequinar, a highly protein-bound antitumor agent [13].
• From the IC50 values, it was deduced that brequinar was a more potent inhibitor of the human dihydroorotate dehydrogenase activity (IC50 = 10 nM) than of the rat enzyme (IC50 = 367 nM) [14].
• Brequinar plasma AUC and the per cent change in platelet count at nadir were correlated (P < 0.001) [15].

Anatomical context of Biphenquinate

• Using in vitro proliferation assays wherein human lymphocytes were triggered by phytohemagglutin, anti-CD3 monoclonal antibody, or mixed lymphocyte reactions, CsA was shown to display additive interactions with 6-mercaptopurine (6-MP), mizorbine (MZB), and mycophenolic acid (MPA), and a synergistic interaction with brequinar (BQR) [16].
• These results may provide a plausible explanation for the findings of other laboratories with cultured cell lines and lymphocytes: in comparison to cells derived from human tissues, rat and other rodent cells were more susceptible to the isoxazol derivatives and less susceptible to brequinar [14].
• The Ki's for NSC 665564 and brequinar were 0.14 and 0.24 microM, respectively, when partially purified MOLT-4 mitochondria (the site of DHO-DH) were used [17].
• Upon analysis of cytotoxicity results from the sixty tumor cell lines used in this screen, the COMPARE program predicted that NSC 665564 was likely to have the same mechanism of inhibition as brequinar, a known potent inhibitor of DHO-DH [17].
• We sought to examine the impact of the preferential activation of Th2 cells on the induction and maintenance of a tolerant state in heart allograft rat recipients treated with a short course of cyclosporine (CsA), sirolimus (SRL) or brequinar (BQR) [18].

Associations of Biphenquinate with other chemical compounds

• Sodium salicylate also altered the pharmacokinetics of i.v. brequinar in rats when adminstered i.v. or p.o. at 10- or 50-fold higher doses than brequinar [13].
• The complete growth pattern of the tumor cells (increase in cell number and protein, RNA and DNA content of cultures during a 24-hr culture period) was examined (i) on reducing the O2 tension of the atmosphere stepwise from 20 to 1% O2; (ii) on addition of 0.125 microM Brequinar; and (iii) under both conditions [19].
• 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) [20].
• The first crystal structure of the class 2 dihydroorotate dehydrogenase from rat has been determined in complex with its two inhibitors brequinar and atovaquone [21].
• Moreover, the complete N-terminal part of the human enzyme seemed to be of crucial importance for the 'slow-binding' features of the cinchoninic acid derivative brequinar, which was suggested to be one of the reasons for the narrow therapeutic window reported from clinical trials on its anti-proliferative and immunosuppressive action [22].

Gene context of Biphenquinate

• Active site of DHODH is mainly hydrophobic and the binding mode of the inhibitor brequinar was used as a template for evaluating the docking strategies [23].
• The present kinetic data on the action of the purified rodent DHO-DH with Brequinar and computer-aided analyses provide a better insight into the drug-enzyme interaction [24].
• Intracellular cytidine triphosphate (CTP) and uridine triphosphate (UTP) pools, free TS binding sites, and levels of free fluorodeoxyuridine monophosphate (FdUMP) and deoxyuridine monophosphate (dUMP) were measured in cells pretreated with 0.1 microM brequinar for 24 h alone or followed by a 2-h exposure to FU (25 microM) +/- LV (100 microM) [25].
• Brequinar, DUP 785, is a substituted 4-quinoline carboxylic acid derivative which in preclinical studies has shown broad antitumor activity [26].

Analytical, diagnostic and therapeutic context of Biphenquinate

• Plasma and urine levels of Brequinar were quantified by high pressure liquid chromatography in 28 patients [12].
• The development of Brequinar as an immunosuppressive drug for transplantation [7].
• The synergistic effects of cyclosporine, sirolimus, and brequinar on heart allograft survival in mice [27].
• In addition, we failed to observe brequinar binding to E.orotate by isothermal titration calorimetry (ITC) [8].
• Here we examine the use of brequinar (BQR) for this purpose and the efficacy of two new reagents developed to demonstrate the establishment of chimerism in the xenograft recipients [28].

References