Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo.
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.
Department of Cell Biology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert, Ann Arbor, Michigan 48105, USA.
J S
JS
Sebolt-Leopold
D T
DT
Dudley
R
R
Herrera
K
K
Van Becelaere
A
A
Wiland
R C
RC
Gowan
H
H
Tecle
S D
SD
Barrett
A
A
Bridges
S
S
Przybranowski
W R
WR
Leopold
A R
AR
Saltiel
D000818:Animals; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D015820:Cadherins / Q000032:analysis; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D001549:Benzamides; D015820:Cadherins; D004791:Enzyme Inhibitors; D017228:Hepatocyte Growth Factor; D017871:Calcium-Calmodulin-Dependent Protein Kinases