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4.
Mol Cancer Ther ; 9(1): 145-56, 2010 Jan.
Article in English | MEDLINE | ID: mdl-20053776

ABSTRACT

Localized angiopoietin-2 (Ang2) expression has been shown to function as a key regulator of blood vessel remodeling and tumor angiogenesis, making it an attractive candidate for antiangiogenic therapy. A fully human monoclonal antibody (3.19.3) was developed, which may have significant pharmaceutical advantages over synthetic peptide-based approaches in terms of reduced immunogenicity and increased half-life to block Ang2 function. The 3.19.3 antibody potently binds Ang2 with an equilibrium dissociation constant of 86 pmol/L, leading to inhibition of Tie2 receptor phosphorylation in cell-based assays. In preclinical models, 3.19.3 treatment blocked blood vessel formation in Matrigel plug assays and in human tumor xenografts. In vivo studies with 3.19.3 consistently showed broad antitumor activity as a single agent across a panel of diverse subcutaneous and orthotopic xenograft models. Combination studies of 3.19.3 with cytotoxic drugs or anti-vascular endothelial growth factor agents showed significant improvements in antitumor activity over single-agent treatments alone with no apparent evidence of increased toxicity. Initial pharmacokinetic profiling studies in mice and nonhuman primates suggested that 3.19.3 has a predicted human half-life of 10 to 14 days. These studies provide preclinical data for 3.19.3 as a potential new antiangiogenic therapy as a single agent or in combination with chemotherapy or vascular endothelial growth factor inhibitors for the treatment of cancer.


Subject(s)
Angiopoietin-2/immunology , Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Vascular Endothelial Growth Factors/antagonists & inhibitors , Xenograft Model Antitumor Assays , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/pharmacokinetics , Antibodies, Monoclonal/therapeutic use , Antibody Specificity/drug effects , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Cell Death/drug effects , Collagen/metabolism , Drug Combinations , Humans , Laminin/metabolism , Mice , Neovascularization, Pathologic/drug therapy , Phosphorylation/drug effects , Primates , Protein Binding/drug effects , Proteoglycans/metabolism , Receptor, TIE-2/metabolism
5.
Bioorg Med Chem Lett ; 19(23): 6670-4, 2009 Dec 01.
Article in English | MEDLINE | ID: mdl-19854647

ABSTRACT

The SAR and improvement in potency against Tie2 of novel thienopyrimidine and thiazolopyrimidine kinase inhibitors are reported. The crystal structure of one of these compounds bound to the Tie-2 kinase domain is consistent with the SAR. These compounds have moderate potency in cellular assays of Tie-2 inhibition, good physical properties, DMPK, and show evidence of in vivo inhibition of Tie-2.


Subject(s)
Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Receptor, TIE-2/antagonists & inhibitors , Thiazoles/pharmacology , Crystallography, X-Ray , Drug Design , Humans , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Stereoisomerism , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistry
6.
Bioorg Med Chem Lett ; 18(16): 4723-6, 2008 Aug 15.
Article in English | MEDLINE | ID: mdl-18676144

ABSTRACT

Tie-2 is a receptor tyrosine kinase which is involved in angiogenesis and thereby growth of human tumours. The discovery and SAR of a novel class of imidazole-vinyl-pyrimidine kinase inhibitors, which inhibit Tie-2 in vitro is reported. Their synthesis was carried out by condensation of imidazole aldehydes with methyl pyrimidines. These compounds are lead-like, with low molecular weight, good physical properties and oral bioavailability.


Subject(s)
Imidazoles/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Receptor, TIE-2/antagonists & inhibitors , Administration, Oral , Biological Availability , Chemistry, Pharmaceutical/methods , Drug Design , Humans , Imidazoles/administration & dosage , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Neovascularization, Pathologic , Protein Kinase Inhibitors/administration & dosage , Pyrimidines/administration & dosage , Receptor, TIE-2/chemistry , Structure-Activity Relationship
8.
Nat Med ; 9(9): 1215-9, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12925849

ABSTRACT

Fusion of tumor cells with antigen-presenting cells (APCs) has been proposed for the preparation of cancer vaccines. However, generation of these hybrids, using physical or chemical methods such as electrofusion or polyethylene glycol (PEG), has been difficult to standardize. Characterization of cell fusion has also been problematic because of difficulties in differentiating fusion from cell aggregation, leakage of cellular dyes and dendritic-cell (DC) phagocytosis of tumor material. In this report, we describe a new method to generate hybrid cell vaccines, based on gene transfer of a viral fusogenic membrane glycoprotein (FMG) into tumor cells, and incorporate a genetic method by which true hybrid formation can be unambiguously detected. We describe a new class of tumor cell-DC hybrid that can be rapidly isolated after cell fusion. These hybrids are highly potent in in vitro antigen presentation assays, target lymph nodes in vivo and are powerful immunogens against established metastatic disease.


Subject(s)
Cancer Vaccines/genetics , Dendritic Cells/cytology , Genetic Techniques , Animals , Antigens, Neoplasm , Cancer Vaccines/immunology , Cancer Vaccines/pharmacology , Cell Fusion/methods , Dendritic Cells/physiology , Glycoproteins/genetics , Hybrid Cells , Lymph Nodes/pathology , Melanoma/genetics , Melanoma/pathology , Melanoma/therapy , Mice , Mice, Inbred C57BL , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/metabolism , T-Lymphocytes/immunology , Tumor Cells, Cultured , Vaccination
9.
Cancer Gene Ther ; 9(11): 897-907, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12386828

ABSTRACT

Carboxypeptidase G2 (CPG2) is a powerful prodrug-converting enzyme. Without a requirement for endogenous enzymes or cofactors, it can directly activate mustard alkylating prodrugs to cytotoxic species, killing both quiescent and dividing cells. This paper provides the first report of its use in the context of a clinically relevant delivery vehicle using adenovirus vectors. To strengthen the efficacy of the prodrug-activating system, the enzyme has been engineered to be secreted or glycosylphosphatidylinositol (GPI) anchored to the extracellular membrane of tumor cells, resulting in an enhanced bystander effect by facilitating diffusion of the active drug through extracellular, rather than intracellular, activation. Using the vectors, we have achieved expression of functional secreted or GPI-anchored CPG2 in a panel of tumor cell lines demonstrating no loss in efficacy as a result of GPI anchor retention. Despite variable transduction efficiencies inherent to these vectors, greater than 50% cell kill was achievable in all of the cell lines tested following only a single exposure to the prodrug ZD2767P. Even in cell lines refractive to infection with the vectors, substantial cell death was recorded, indicative of the enhanced bystander effect generated following extracellular prodrug activation. A direct evaluation of the efficacy of our system has been made against adenoviral delivery of herpes simples virus thymidine kinase plus ganciclovir (GCV), a suicide gene therapy approach already in the clinic. In a short-term human glioma culture (IN1760) resistant to the clinical chemotherapeutic drug CCNU (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea), thymidine kinase/GCV effected no cell killing compared to 70% cell killing with our system.


Subject(s)
Cell Membrane/enzymology , gamma-Glutamyl Hydrolase/genetics , Adenoviridae/genetics , Amino Acid Sequence , Animals , Base Sequence , Cell Survival , DNA Primers , Exons , Genetic Vectors , Glycosylphosphatidylinositols/metabolism , Humans , Molecular Sequence Data , Mutagenesis, Site-Directed , Prodrugs/metabolism , Rats , Recombinant Fusion Proteins/metabolism , Thy-1 Antigens/genetics , Transfection , Tumor Cells, Cultured , gamma-Glutamyl Hydrolase/metabolism
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