Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo

• Published in: Nature medicine Vol. 5; no. 7; pp. 810 - 816
• Main Authors: Sebolt-Leopold, Judith S, Dudley, David T, Herrera, Roman, Becelaere, Keri Van, Wiland, Amy, Gowan, Richard C, Tecle, Haile, Barrett, Stephen D, Bridges, Alexander, Przybranowski, Sally, Leopold, W.R, Saltiel, Alan R
• Format: Journal Article
• Language: English
• Published: United States 01-07-1999
• Subjects: Animals; Benzamides - pharmacology; Benzamides - therapeutic use; Cadherins - analysis; Calcium-Calmodulin-Dependent Protein Kinases - antagonists & inhibitors; Cell Cycle - drug effects; Cell Division - drug effects; Colonic Neoplasms - drug therapy; Colonic Neoplasms - enzymology; Colonic Neoplasms - pathology; Colonic Neoplasms - physiopathology; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Female; Hepatocyte Growth Factor - pharmacology; Humans; Male; Mice; Mice, Inbred Strains; Mice, Nude; Neoplasm Invasiveness - prevention & control; Signal Transduction - drug effects; Transplantation, Heterologous; Tumor Cells, Cultured
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/10533

The mitogen-activated protein kinase pathway is thought to be essential in cellular growth and differentiation. Here we report the discovery of a highly potent and selective inhibitor of the upstream kinase MEK that is orally active. Tumor growth was inhibited as much as 80% in mice with colon carcinomas of both mouse and human origin after treatment with this inhibitor. Efficacy was achieved with a wide range of doses with no signs of toxicity, and correlated with a reduction in the levels of activated mitogen-activated protein kinase in excised tumors. These data indicate that MEK inhibitors represent a promising, noncytotoxic approach to the clinical management of colon cancer.