Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a European joint project carried out in 6 laboratories a disease-oriented program was set up consisting of a panel of 7 tumor types, each represented by 4 to 8 different human tumor lines, for secondary screening of promising anticancer drugs. Human tumor lines were selected on the basis of differences in histology, growth rate, and sensitivity to conventional cytostatic agents. Xenografts were grown s.c. in nude mice, and treatment was started when tumors reached a mean diameter of 6 mm in groups of mice where at least 6 tumors were evaluable. Drugs were given at the maximum tolerated dose. For evaluation of drug efficacy, median tumor growth curves were drawn, and specific growth delay and treated/control x 100% were calculated. Doxorubicin (8 mg/kg i.v. days 1 and 8) was effective (treated/control < 50%, and specific growth delay > 1.0) in 0 of 2 breast cancers, 1 of 3 colorectal cancers, 2 of 5 head and neck cancers, 3 of 6 non-small cell lung cancers, 4 of 6 small cell lung cancers, 0 of 3 melanomas, and 3 of 6 ovarian cancer lines. Amsacrine (8 mg/kg i.v. days 1 and 8) was not effective, while datelliptium (35 mg/kg i.p. days 1 and 8) was active against 2 of 6 small cell lung cancer lines. 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. The project has been shown to be a feasible approach. Clinical activity for doxorubicin and inactivity for amsacrine against solid tumor types was confirmed in the human tumor xenograft panel. Additional anticancer drugs will be studied in the European joint project to further define the reliability of this novel, promising screening approach.
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PMID:Phase II preclinical drug screening in human tumor xenografts: a first European multicenter collaborative study. 139 20

The effect of Brequinar sodium on the growth of xenografts established from head and neck squamous cell carcinomas (HNSCC) was assessed. Brequinar sodium is a novel drug, known to inhibit dihydroorotic acid dehydrogenase (DHO-DH), resulting in a decrease of the pyrimidine de novo synthesis. The drug was administered i.p. to tumor-bearing nude mice, once a day, during 5 days at a maximum tolerated dose of 50 mg/kg/day. Statistically significant growth delaying effects were observed in 4 out of 5 lines tested. In 3 of these lines the effect was moderate and short lasting, whereas in one line (HNX-LP) tumor growth rate was totally inhibited for a 17-day period. In this line, Brequinar sodium was superior to 5 drugs known to be active in HNSCC patients. In two tumor lines DHO-DH activity could be measured and the results are in agreement with the concept that there is a relation between Brequinar sodium sensitivity and enzyme activity.
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PMID:Antitumor activity of brequinar sodium (Dup-785) against human head and neck squamous cell carcinoma xenografts. 230 6

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.
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PMID:Phase I and pharmacokinetic study of brequinar sodium (NSC 368390). 236 34

Vascular endothelial growth factor (VEGF) is a potent angiogenesis inducer for tumor growth and angiogenesis. Benzo[a]pyrene (BaP) belongs to polycyclic aromatic hydrocarbons (PAHs) and is known to cause carcinogenesis. But the effects of BaP and its metabolites on VEGF and HIF-1 expression remain to be elucidated. In this study, we found benzo[a]pyrene-3,6-dione (BPQ), but not BaP and benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE) inhibited VEGF expression in a dose-dependent manner. BPQ inhibited VEGF transcriptional activation through hypoxia-inducible factor 1 (HIF-1) binding site. BPQ specifically decreased HIF-1alpha, but not HIF-1beta subunit expression in A549 cells. We found that BPQ did not inhibit HIF-1alpha mRNA level, but inhibited its protein expression in a proteasome-dependent manner. To further clarify the mechanism of BPQ in regulating HIF-1alpha stability, we found that BPQ inhibited HIF-1alpha protein expression by the increase of the proteasome-dependent degradation, and by the disruption of HIF-1alpha and Hsp90 association.
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PMID:Benzo[a]pyrene-3,6-dione inhibited VEGF expression through inducing HIF-1alpha degradation. 1744 77