TY - JOUR
T1 - Phase I study of Brequinar sodium (NSC 368390) in patients with solid malignancies
AU - Schwartsmann, Gilberto
AU - Dodion, Pierre
AU - Vermorken, Jan B.
AU - ten Bokkel Huinink, Wim W.
AU - Joggi, Jean
AU - Winograd, Benjamin
AU - Gall, Helen
AU - Simonetti, Godeleine
AU - van der Vijgh, Wim J F
AU - van Hennik, Maike B.
AU - Crespeigne, Nadine
AU - Pinedo, Herbert M.
PY - 1990/9
Y1 - 1990/9
N2 - 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. This compound inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHO-DH), which catalyzes the conversion of dihydroorotate to orotate, leading to a blockage in the pyrimidine de novo biosynthesis. A total of 43 patients received 110 courses of Brequinar sodium by short-term intravenous (i. v.) infusion, which was repeated every 3 weeks. Dose escalation was initially based on a modified Fibonacci scheme. After pharmacokinetic data from mice and man became available, a pharmacologically guided dose escalation was used; at toxic levels, dose escalation was applied on the basis of clinical judgement. The dose-limiting toxicities were myelosuppression, mucositis, skin rash, nausea and vomiting. The maximum tolerable doses for poor- and good-risk patients were 1,500 and 2,250 mg/m2, respectively. One mixed response was observed in a patient with papilary carcinoma of the thyroid. The recommended doses for phase II studies are 1,200 and 1,800 mg/m2 Brequinar sodium, given by a 1-h i.v. infusion every 3 weeks to poor- and good-risk patients, respectively.
AB - 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. This compound inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHO-DH), which catalyzes the conversion of dihydroorotate to orotate, leading to a blockage in the pyrimidine de novo biosynthesis. A total of 43 patients received 110 courses of Brequinar sodium by short-term intravenous (i. v.) infusion, which was repeated every 3 weeks. Dose escalation was initially based on a modified Fibonacci scheme. After pharmacokinetic data from mice and man became available, a pharmacologically guided dose escalation was used; at toxic levels, dose escalation was applied on the basis of clinical judgement. The dose-limiting toxicities were myelosuppression, mucositis, skin rash, nausea and vomiting. The maximum tolerable doses for poor- and good-risk patients were 1,500 and 2,250 mg/m2, respectively. One mixed response was observed in a patient with papilary carcinoma of the thyroid. The recommended doses for phase II studies are 1,200 and 1,800 mg/m2 Brequinar sodium, given by a 1-h i.v. infusion every 3 weeks to poor- and good-risk patients, respectively.
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U2 - 10.1007/BF00686235
DO - 10.1007/BF00686235
M3 - Article
C2 - 2306795
AN - SCOPUS:0025022293
SN - 0344-5704
VL - 25
SP - 345
EP - 351
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 5
ER -