ABSTRACT
BACKGROUND: TB-403 (RO 5323441), a humanised monoclonal antibody, is a novel antiangiogenesis agent directed against placental growth factor. The safety, pharmacokinetics (PK), and antitumour activity of TB-403 were assessed in a phase I, dose-escalation study in patients with advanced solid tumours. METHODS: Patients in sequential dose groups received either weekly doses of 1.25, 5.0, or 10 mg kg(-1) or doses of 20 or 30 mg kg(-1) every third week. RESULTS: Twenty-three patients were enrolled and received TB-403. The most common adverse events (AEs) were fatigue, constipation, pyrexia, dyspnoea, and nausea. One serious AE, a lung embolus in a patient with non-small cell lung cancer treated with 10 mg kg(-1) weekly, was deemed possibly related to TB-403. No dose-limiting toxicities were observed, and a maximum-tolerated dose was not reached. The PK parameters were dose linear and the terminal half-life values ranged from 9 to 14 days. Six patients exhibited stable disease for at least 8 weeks. Two patients, (oesophageal squamous cell carcinoma and pancreatic adenocarcinoma) both treated with 5 mg kg(-1) weekly, remained stable for 12 months. CONCLUSION: TB-403 treatment in this patient population is well tolerated, with a safety profile distinct from that of vascular endothelial growth factor-axis inhibitors.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antibodies, Monoclonal/therapeutic use , Neoplasms/drug therapy , Pregnancy Proteins/immunology , Adult , Aged , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/adverse effects , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/pharmacokinetics , Antibodies, Monoclonal, Humanized/administration & dosage , Drug Administration Schedule , Female , Humans , Infusions, Intravenous , Male , Maximum Tolerated Dose , Middle Aged , Placenta Growth FactorABSTRACT
The gram-positive endospore-forming bacterium Bacillus subtilis has, under aerobic conditions, a branched respiratory system comprising one quinol oxidase branch and one cytochrome oxidase branch. The system terminates in one of four alternative terminal oxidases. Cytochrome caa(3) is a cytochrome c oxidase, whereas cytochrome bd and cytochrome aa(3) are quinol oxidases. A fourth terminal oxidase, YthAB, is a putative quinol oxidase predicted from DNA sequence analysis. None of the terminal oxidases are, by themselves, essential for growth. However, one quinol oxidase (cytochrome aa(3) or cytochrome bd) is required for aerobic growth of B. subtilis strain 168. Data indicating that cytochrome aa(3) is the major oxidase used by exponentially growing cells in minimal and rich medium are presented. We show that one of the two heme-copper oxidases, cytochrome caa(3) or cytochrome aa(3), is required for efficient sporulation of B. subtilis strain 168 and that deletion of YthAB in a strain lacking cytochrome aa(3) makes the strain sporulation deficient.
Subject(s)
Bacillus subtilis/enzymology , Cytochromes/metabolism , Electron Transport Chain Complex Proteins , Electron Transport Complex IV/metabolism , Escherichia coli Proteins , Oxidoreductases/metabolism , ATP-Binding Cassette Transporters/genetics , ATP-Binding Cassette Transporters/physiology , Aerobiosis , Bacillus subtilis/genetics , Bacillus subtilis/growth & development , Bacillus subtilis/physiology , Cytochrome b Group , Cytochromes/genetics , Electron Transport Complex IV/genetics , Genes, Bacterial , Isopropyl Thiogalactoside/pharmacology , Mutagenesis , Operon , Oxidoreductases/genetics , Promoter Regions, Genetic/drug effects , Spores, Bacterial/physiologyABSTRACT
We have cloned an Enterococcus faecalis gene cluster, cydABCD, which when expressed in Bacillus subtilis results in a functional cytochrome bd terminal oxidase. Our results indicate that E. faecalis V583 cells have the capacity of aerobic respiration when grown in the presence of heme.
Subject(s)
Cytochromes/genetics , Electron Transport Chain Complex Proteins , Enterococcus faecalis/enzymology , Escherichia coli Proteins , Genes, Bacterial , Multigene Family , Oxidoreductases/genetics , Bacillus subtilis/genetics , Bacillus subtilis/metabolism , Cytochrome b Group , Enterococcus faecalis/genetics , Gene Expression , Genetic Complementation Test , MutagenesisABSTRACT
Under aerobic conditions Bacillus subtilis utilizes a branched electron transport chain comprising various cytochromes and terminal oxidases. At present there is evidence for three types of terminal oxidases in B. subtilis: a caa3-, an aa3-, and a bd-type oxidase. We report here the cloning of the structural genes (cydA and cydB) encoding the cytochrome bd complex. Downstream of the structural genes, cydC and cydD are located. These genes encode proteins showing similarity to bacterial ATP-binding cassette (ABC)-type transporters. Analysis of isolated cell membranes showed that inactivation of cydA or deletion of cydABCD resulted in the loss of spectral features associated with cytochrome bd. Gene disruption experiments and complementation analysis showed that the cydC and cydD gene products are required for the expression of a functional cytochrome bd complex. Disruption of the cyd genes had no apparent effect on the growth of cells in broth or defined media. The expression of the cydABCD operon was investigated by Northern blot analysis and by transcriptional and translational cyd-lacZ fusions. Northern blot analysis confirmed that cydABCD is transcribed as a polycistronic message. The operon was found to be expressed maximally under conditions of low oxygen tension.
