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At least 235 records · Page 13Linked to original sources
PubMed1992

Brequinar potentiates 5-fluorouracil antitumor activity in a murine model colon 38 tumor by tissue-specific modulation of uridine nucleotide pools.

Modulation of pyrimidine metabolism or the metabolic fate of 5-fluorouracil by a number of different agents has permitted a significant increase in the response rate to this agent, particularly for colorectal cancers. Brequinar, a noncompetitive inhibitor of mitochondrial dihydroorotate dehydrogenase has been shown to achieve a tumor-specific modulation of the therapeutic effect of 5-fluorouracil. A selective decrease of uridine nucleotide pools in Colon tumor 38 compared to normal tissues of C57/BL6 mice was observed after Brequinar administration. This effect was achieved with very low nontherapeutic doses of Brequinar (8 to 27% of the maximum tolerated dose in this model). Pretreatment with Brequinar 4 and 24 h prior to administration of [3H]fluorouracil significantly increased incorporation of the fluoropyrimidine into Colon 38 tumor RNA, while minimal effects were seen in normal tissues of C57/BL6 mice. Brequinar (15, 30, and 50 mg/kg) was administered 4 h prior to fluorouracil (85 mg/kg) on a weekly basis in Colon 38-bearing mice. All combinations potentiated 5-fluorouracil antitumor activity and the lowest dose of Brequinar (15 mg/kg) showed a reduced toxicity (weight loss) compared to the same dose of 5-fluorouracil as a single agent. When Brequinar preceded fluorouracil by 24 h, greater toxicity and less antitumor activity were observed. A comparison of the optimal Brequinar-fluorouracil regimen with a previously optimized N-(phosphonoacetyl)-L-aspartic acid-fluorouracil combination in Colon 38 tumor indicated that Brequinar-fluorouracil was more effective and less toxic.

Animals↗
PubMed1992

Inhibition of dihydroorotate dehydrogenase activity by brequinar sodium.

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. Brequinar sodium inhibits the activity of this enzyme isolated from mammalian sources only but not those forms isolated from yeast or bacteria, which also use ubiquinone as the cofactor. Brequinar sodium also does not inhibit the activity of a soluble Zymobacterium oroticum dihydroorotate dehydrogenase which uses NAD+ as a cofactor. Brequinar sodium inhibits L1210 dihydroorotate dehydrogenase with mixed inhibition kinetics with respect to either the substrate (dihydroorotate) or the cofactor (ubiquinone Q6) with Ki' values in the 5-8 nM range. Our results suggest that brequinar sodium inhibits dihydroorotate dehydrogenase by binding to the enzyme at a unique site that is distinct from the dihydroorotate or the ubiquinone-binding site. 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.

Animals↗
PubMed1990

Effects of brequinar and ciprofloxacin on de novo nucleotide biosynthesis in mouse L1210 leukemia.

Exposure of mouse L1210 leukemia cells to 25 microM brequinar for 4 h results in large accumulations of N-carbamyl-L-aspartate and L-dihydroorotate to cellular concentrations of 8.5 mM and 0.8 mM, respectively, while UTP and CTP decrease to 4% of their initial levels; incorporation of [14C]bicarbonate into nucleic acids (DNA and RNA) was decreased to 47%. These data provide direct evidence for inhibition of DHO dehydrogenase by brequinar in growing cells. Exposure of leukemia cells to 200 microM ciprofloxacin for 4 h did not affect de novo pyrimidine nucleotide biosynthesis or the incorporation of [14C]bicarbonate into nucleic acids but resulted in a general decrease in nucleoside triphosphates, with concomitant accumulation of nucleoside mono- and diphosphates (the adenylate energy charge decreased from 0.89 to 0.69), consistent with inhibition of the electron transport chain or uncoupling of oxidative phosphorylation.

Animals↗
PubMed1990

In vivo inhibition of the pyrimidine de novo enzyme dihydroorotic acid dehydrogenase by brequinar sodium (DUP-785; NSC 368390) in mice and patients.

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). In addition to the measurement of plasma uridine concentrations, we also measured in lymphocytes of 9 patients (10 courses) the duration of DHO-DH inhibition. Brequinar sodium was administered every 3 weeks as an i.v. infusion at dose levels of 15-2250 mg/m2. The biochemical effects were studied following the first administration of the drug. In sonicated extracts of lymphocytes from 7 healthy volunteers the activity of DHO-DH varied from 2.0 to 3.9 nmol/h per 10(6) cells, while in the lymphocytes of 9 patients obtained immediately before treatment this value was between 0.5 and 4.8 nmol/h per 10(6) cells. Within 15 min of drug administration DHO-DH activity was not detectable and was still low up to 1 week later. Duration of the inhibition appeared to be related to the extent of clinical toxicity, e.g., myelosuppression, nausea, vomiting, diarrhea, and mucositis. Severe lymphopenia was observed in patients receiving Brequinar sodium at the maximum tolerated dose. 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.

Animals↗
PubMed1990

Effects of plasma protein binding displacement on the pharmacokinetics, tissue and tumor concentrations and efficacy of brequinar, a highly protein-bound antitumor agent.

Brequinar is a developmental antitumor agent which is highly bound to plasma proteins. The effects of plasma protein binding displacement on brequinar pharmacokinetics, tissue distribution, tumor distribution and antitumor efficacy were evaluated. Sodium salicylate and ibuprofen increased the percentage of free brequinar in serum in vitro, in proportion to their added concentrations. 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. At the highest salicylate/brequinar dose ratio, significant increases were observed for terminal half-life, mean residence times in the body and tissues, systemic clearance, distribution clearance, the volume of the central compartment and volume of distribution at steady state. Neither salicylate nor ibuprofen increased brequinar concentrations in lung and muscle specimens from rats, 4 or 24 hr after dosing. Tumor, lung and muscle brequinar concentrations in mice were also unaffected by coadministered sodium salicylate, 4 or 24 hr after a single i.v. brequinar dose. In rats infused for 48 hr with brequinar or brequinar plus salicylate, salicylate increased the percentage of free brequinar in plasma and lungs, but total brequinar concentrations were reduced. Antitumor efficacy was evaluated by measuring the survival times of mice implanted with L1210 leukemia cells. Salicylate-treated mice had a similar brequinar dose/response profile as mice not coadministered salicylate. Ibuprofen also did not increase brequinar's antitumor potency.

Animals↗
PubMed1990

Phase I and pharmacokinetic study of brequinar sodium (NSC 368390).

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. This phase I study evaluated the administration of brequinar sodium by short, daily i.v. infusion for 5 days repeated every 4 weeks. Fifty-four subjects were enrolled in the study and received drug in doses ranging from 36-300 mg/m2. The dose-limiting toxicities were mucositis and diffuse skin rash. Other toxicities included myelosuppression, nausea, vomiting, malaise, and burning at the infusion site. The maximum tolerated dose on the "daily times 5" schedule was 300 mg/m2. The recommended phase II dose is 250 mg/m2. Pharmacokinetic analysis of the day 1 drug clearance curves in 51 subjects showed slight nonlinearity in the relationship between dose and area under the clearance curve (AUC). 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. 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.

Antineoplastic Agents↗
PubMed1989

Phase I clinical and pharmacokinetic trial of Brequinar sodium (DuP 785; NSC 368390).

Brequinar sodium is a 4-quinolinecarboxylic acid analogue that inhibits dihydroorotate dehydrogenase and subsequent de novo pyrimidine biosynthesis. It has shown dose-dependent antineoplastic activity against several mouse and human tumor models. This trial evaluated Brequinar given as a single daily i.v. bolus over a 5-day period repeated every 28 days. One hundred seven courses of treatment at dosages ranging from 36 to 300 mg/m2/day x 5 were administered to 45 patients (31 male and 14 female) with refractory solid tumors; median age was 58 years (range 30-74); median Southwest Oncology Group performance status was 1 (range, 0-3). Thirty patients had prior cytotoxic chemotherapy. Dose-limiting toxicities were thrombocytopenia and a severe desquamative maculopapular dermatitis. Two of 5 good risk patients at 300 mg/m2 and 3 of 6 poor risk patients at 170 mg/m2 developed a platelet count less than 25 x 10(3)/microliters. Two of 5 good risk patients at 300 mg/m2 and 1 of 6 poor risk patients at 170 mg/m2 developed a severe desquamative dermatitis. Moderate to severe mucositis was usually associated with the thrombocytopenia and/or the dermatitis. Nonhematological drug-related toxicities included nausea and vomiting, malaise, anorexia, diarrhea, phlebitis, reversible transaminase elevation, and mucositis. Other hematological toxicities were anemia, granulocytopenia, and leukopenia. There were no drug-related deaths. There were no objective tumor responses. Plasma and urine levels of Brequinar were quantified by high pressure liquid chromatography in 28 patients. Plasma levels and areas under the curve increased proportionally with increased dose. Brequinar had a harmonic mean terminal t1/2 of 8.1 +/- 3.6 h with a model-independent determined apparent volume of distribution at steady state of 9.0 +/- 2.9 liters/m2 and a total body clearance of 19.2 +/- 7.7 ml/min/m2. Renal excretion was a minor route of elimination for Brequinar. The maximally tolerated dose of Brequinar on a daily x 5 i.v. schedule was 250 mg/m2 for good risk patients. For the daily x 5 i.v. schedule, the recommended dose of Brequinar for phase II evaluation is 250 mg/m2 for good risk patients and 135 mg/m2 for poor risk patients.

Adult↗
PubMed1986

[Sensitivity of fungi in the genus Candida to antimicrobial preparations].

Sensitivity of 50 Candida fungus strains isolated from patients with chronic intestine diseases was studied with respect to amphotericin B, levorin, enteroseptol, intestopan and decamethoxin. The rate of forming resistant variants of the strains with respect to decamethoxin and development of their cross resistance to levorin was estimated. It was shown that decamethoxin was the most active antifungal drug among the drugs tested. Estimation of sensitivity of the Candida strains to enteroseptol and intestopan revealed that the fungicidal concentration of enteroseptol for 78 per cent of the strains ranged within 3.9-7.8 micrograms/ml. It was demonstrated that development of resistance to decamethoxin in the strains of Candida albicans was slow and did not reach high levels. No cross resistance between decamethoxin and levorin was detected.

Amphotericin B↗