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2.
Bioorg Med Chem Lett ; 16(21): 5633-8, 2006 Nov 01.
Article in English | MEDLINE | ID: mdl-16934457

ABSTRACT

A new class of pyrimidine-based Janus tyrosine kinase 3 (JAK3) inhibitors are described. Many of these inhibitors showed low nanomolar activity against JAK3.


Subject(s)
Janus Kinase 3/antagonists & inhibitors , Pyrimidines/chemistry , Pyrimidines/pharmacology
3.
Cancer Res ; 63(12): 3145-53, 2003 Jun 15.
Article in English | MEDLINE | ID: mdl-12810642

ABSTRACT

To evaluate whether beta-catenin signaling has a role in the regulation of angiogenesis in colon cancer, a series of angiogenesis-related gene promoters was analyzed for beta-catenin/TCF binding sites. Strikingly, the gene promoter of human vascular endothelial growth factor (VEGF, or VEGF-A) contains seven consensus binding sites for beta-catenin/TCF. Analysis of laser capture microdissected human colon cancer tissue indicated a direct correlation between up-regulation of VEGF-A expression and adenomatous polyposis coli (APC) mutational status (activation of beta-catenin signaling) in primary tumors. In metastases, this correlation was not observed. Analysis by immunohistochemistry of intestinal polyps in mice heterozygous for the multiple intestinal neoplasia gene (Min/+) at 5 months revealed an increase and redistribution of VEGF-A in proximity to those cells expressing nuclear beta-catenin with a corresponding increase in vessel density. Transfection of normal colon epithelial cells with activated beta-catenin up-regulated levels of VEGF-A mRNA and protein by 250-300%. When colon cancer cells with elevated beta-catenin levels were treated with beta-catenin antisense oligodeoxynucleotides, VEGF-A expression was reduced by more than 50%. Taken together, our observations indicate a close link between beta-catenin signaling and the regulation of VEGF-A expression in colon cancer.


Subject(s)
Adenocarcinoma/genetics , Colonic Neoplasms/genetics , Cytoskeletal Proteins/physiology , Endothelial Growth Factors/biosynthesis , Gene Expression Regulation, Neoplastic/physiology , Intercellular Signaling Peptides and Proteins/biosynthesis , Lymphokines/biosynthesis , Neoplasm Proteins/biosynthesis , Promoter Regions, Genetic/genetics , Trans-Activators/physiology , Adenocarcinoma/blood supply , Adenocarcinoma/etiology , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Adenomatous Polyposis Coli/genetics , Adenomatous Polyposis Coli/metabolism , Animals , Binding Sites , Colon/metabolism , Colonic Neoplasms/blood supply , Colonic Neoplasms/etiology , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Cytoskeletal Proteins/genetics , Endothelial Growth Factors/genetics , Fibroblast Growth Factor 2/analysis , Gene Expression Regulation, Neoplastic/drug effects , Genes, APC , Genes, ras , Growth Substances/genetics , Humans , Intercellular Signaling Peptides and Proteins/genetics , Intestinal Mucosa/metabolism , Lymphokines/genetics , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Neoplasm Proteins/genetics , Oligodeoxyribonucleotides, Antisense/pharmacology , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , RNA, Neoplasm/biosynthesis , RNA, Neoplasm/genetics , Recombinant Fusion Proteins/physiology , Signal Transduction , Subcellular Fractions/chemistry , Trans-Activators/genetics , Transfection , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/metabolism , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors , beta Catenin
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