Disease relevance of Dup 785

• Brequinar sodium (50 mg/kg i.p. days 1-5) showed efficacy in 4 of 5 head and neck cancers, 5 of 8 non-small cell lung cancers, and 4 of 5 small cell lung cancer lines [1].
• This binding site appears to be unique to the mammalian enzyme, because brequinar sodium does not inhibit the yeast, Escherichia coli, or Z. oroticum forms of the enzyme [2].
• Severe lymphopenia was observed in patients receiving Brequinar sodium at the maximum tolerated dose [3].
• Multicenter phase II trial of brequinar sodium in patients with advanced melanoma [4].
• The immunosuppressive effect of the novel 4-quinoline carboxylic acid derivative Brequinar sodium on the chronic relapsing experimental allergic encephalomyelitis CREAE model in the Biozzi AB/H mouse was investigated [5].

High impact information on Dup 785

• Inhibition of dihydroorotate dehydrogenase activity by brequinar sodium [2].
• 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 [6].
• Evaluation of cyclosporine, mycophenolate mofetil, and Brequinar sodium combination therapy on hamster-to-rat cardiac xenotransplantation [7].
• Brequinar sodium (BQR) is a new immunosuppressive drug that is highly effective in preventing graft rejection in several different experimental settings, including primary allografts and xenografts [8].
• Novel mechanisms of brequinar sodium immunosuppression on T cell activation [9].

Chemical compound and disease context of Dup 785

• Retention of in vivo antipyrimidine effects of Brequinar sodium (DUP-785; NSC 368390) in murine liver, bone marrow and colon cancer [10].
• Pyrimidine de novo biosynthesis, at the stage of respiratory chain-dependent dihydroorotate dehydrogenase, was found to be a biochemical target site for oxygen deficiency as well as for Brequinar Sodium (6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinoline carboxylic acid sodium salt) (Brequinar) [11].

Biological context of Dup 785

• Brequinar sodium (BQR) is a novel immunosuppressive agent that is highly effective in preventing B lymphocyte-mediated antibody production [12].
• Prevention of orthotopic liver allograft rejection in rats with a short-term brequinar sodium therapy. Analysis of intragraft cytokine gene expression [8].
• This structure-activity relationship study identified three critical regions of brequinar sodium and its analogs, where specific substitutions are required for the inhibition of the activity of dihydroorotate dehydrogenase [13].
• The relation between inhibition of cell growth and of dihydroorotic acid dehydrogenase by brequinar sodium [14].
• Similarly, the IC50 values of another DHODH inhibitor, brequinar sodium, were also attenuated by uridine from 0.04 to 1 microm for IgM, and 0.012 to 10 microm for IgG [15].

Anatomical context of Dup 785

• The antilymphocytic activity of brequinar sodium and its potentiation by cytidine. Effects on lymphocyte proliferation and cytokine production [16].
• Although Brequinar sodium actively inhibited peripheral immune responses, it showed a limited potential to control an ongoing disease of the central nervous system (CNS) [5].
• Therapy of chronic relapsing experimental allergic encephalomyelitis and the role of the blood-brain barrier: elucidation by the action of Brequinar sodium [5].
• Brequinar sodium inhibits interleukin-6-induced differentiation of a human B-cell line into IgM-secreting plasma cells [17].
• The growth inhibitory effects of Brequinar Sodium (DUP-785; NSC 368390) in 7 different cell lines were related to growth rates and to the inhibition of dihydroorotic acid dehydrogenase (DHO-DH) activity [14].

Associations of Dup 785 with other chemical compounds

• The novel anticancer drug candidate brequinar sodium (DuP 785, NSC 368390, 6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinoline- carboxylic acid sodium salt) was shown previously to be an inhibitor of dihydroorotate dehydrogenase, the fourth enzyme of the de novo pyrimidine biosynthetic pathway [2].
• The synergism of brequinar sodium and cyclosporine used in combination to prevent cardiac allograft rejection in the rat [18].
• T and B cells are more sensitive than nonimmune cells to the depletion of purines and pyrimidines caused by mizoribine, mycophenolic acid, and brequinar sodium [19].
• Kinetics of inhibition of human and rat dihydroorotate dehydrogenase by atovaquone, lawsone derivatives, brequinar sodium and polyporic acid [20].
• Therapeutic agents brequinar sodium and leflunomide (Arava) work by binding in a hydrophobic tunnel formed by a highly variable N-terminus of family 2 dihydroorotate dehydrogenase (DHODH) [21].

Gene context of Dup 785

• RESULTS: KF20444 inhibited rat liver dihydroorotate dehydrogenase in vitro with Ki = 8.5 +/- 3.2 nM, which was a comparable effect to that of brequinar sodium (Ki = 25.3 +/- 5.3 nM) [22].
• Differential susceptibility of dihydroorotate dehydrogenase/oxidase to Brequinar Sodium (NSC 368 390) in vitro [23].
• Control of lymphoproliferative and autoimmune disease in MRL-lpr/lpr mice by brequinar sodium: mechanisms of action [24].
• Brequinar sodium (DUP 785, NSC 368390) is a novel quinoline-carboxylic acid derivative that has been selected for clinical evaluation because of its broad spectrum of antitumor activity in animal models and its novel chemical structure [25].

Analytical, diagnostic and therapeutic context of Dup 785

• The preclinical and clinical characterization of Brequinar sodium has demonstrated the potential for the use of this drug as a component of a polytherapeutic treatment strategy to prevent the rejection of organ grafts [26].
• The effect of a new immunosuppressive drug, brequinar sodium, on heart, liver, and kidney allograft rejection in the rat [27].
• The prevention of accelerated cardiac allograft rejection in sensitized recipients after treatment with brequinar sodium [12].
• Eighty-six patients with advanced colorectal, gastric or pancreatic carcinoma and no prior exposure to chemotherapy were treated with brequinar sodium [28].
• The use of brequinar sodium for transplantation [29].

References