Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Phase I clinical and pharmacokinetic trial of Brequinar sodium (DuP 785; NSC 368390). 274 43

Brequinar sodium (BQR) was originally developed as an antitumor drug and subsequently as an immunosuppressant for controlling transplant rejection. It has been widely accepted that the antitumor and immunosuppressive activities of BQR are dependent on its ability to inhibit the enzymatic activity of dihydroorotate dehydrogenase, the fourth enzyme in the de novo pyrimidine synthesis pathway. Recently, we discovered that BQR has the ability to inhibit protein tyrosine phosphorylation in anti-CD3-stimulated murine T lymphocytes and to inhibit the activity of src-related protein tyrosine kinases, p56lck and p59fyn. We examined the in vivo activities of BQR in MRL-lpr/lpr mice. We report that the dose of BQR (10 mg/kg/day) that induced anemia, controlled lymphadenopathy and inhibited autoantibody production, also selectively reduced the pyrimidine nucleotide levels in the bone marrow and in the lymph nodes. Coadministration of uridine (1000 mg/kg/day) with BQR completely normalized pyrimidine nucleotide levels in the bone marrow and lymph nodes, and prevented BQR-induced anemia. However, coadministration of uridine with BQR only partially reversed the anti-proliferative effects of BQR, and did not antagonize the inhibitory effect of BQR on autoantibody production. Finally, we report that BQR markedly reduced protein tyrosine phosphorylation in lymph nodes of MRL-lpr/lpr mice. These results collectively suggest that the control of lymphadenopathy and autoantibody production in MRL-lpr/lpr mice by BQR is only partially dependent on inhibition of pyrimidine nucleotide synthesis, and suggest a critical role for in vivo inhibition of protein tyrosine phosphorylation.
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PMID:Control of lymphoproliferative and autoimmune disease in MRL-lpr/lpr mice by brequinar sodium: mechanisms of action. 935 8