RT Journal Article
SR Electronic
T1 A Vascular Endothelial Growth Factor Receptor-2 Kinase Inhibitor Potentiates the Activity of the Conventional Chemotherapeutic Agents Paclitaxel and Doxorubicin in Tumor Xenograft Models
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 635
OP 647
DO 10.1124/mol.104.000638
VO 66
IS 3
A1 Emanuel, Stuart
A1 Gruninger, Robert H.
A1 Fuentes-Pesquera, Angel
A1 Connolly, Peter J.
A1 Seamon, Jennifer A.
A1 Hazel, Susan
A1 Tominovich, Rose
A1 Hollister, Beth
A1 Napier, Cheryl
A1 D'Andrea, Michael R.
A1 Reuman, Michael
A1 Bignan, Gilles
A1 Tuman, Robert
A1 Johnson, Dana
A1 Moffatt, David
A1 Batchelor, Mark
A1 Foley, Anne
A1 O'Connell, James
A1 Allen, Rodger
A1 Perry, Martin
A1 Jolliffe, Linda
A1 Middleton, Steven A.
YR 2004
UL http://molpharm.aspetjournals.org/content/66/3/635.abstract
AB Inhibition of angiogenesis may have wide use in the treatment of cancer; however, this approach alone will not cause tumor regression but may only slow the growth of solid tumors. The clinical potential of antiangiogenic agents may be increased by combining them with conventional chemotherapeutics. 4-[4-(1-Amino-1-methylethyl)phenyl]-2-[4-(2-morpholin-4-yl-ethyl)phenylamino]pyrimidine-5-carbonitrile (JNJ-17029259) represents a novel structural class of 5-cyanopyrimidines that are orally available, selective, nanomolar inhibitors of the vascular endothelial growth factor receptor-2 (VEGF-R2) and other tyrosine kinases involved in angiogenesis, such as platelet-derived growth factor receptor, fibroblast growth factor receptor, VEGF-R1, and VEGF-R3, but have little activity on other kinase families. At nanomolar levels, JNJ-17029259 blocks VEGF-stimulated mitogen-activated protein kinase signaling, proliferation/migration, and VEGF-R2 phosphorylation in human endothelial cells; inhibits the formation of vascular sprouting in the rat aortic ring model of angiogenesis; and interferes with the development of new veins and arteries in the chorioallantoic membrane assay. At higher concentrations of 1 to 3 μM, this compound shows antiproliferative activity on cells that may contribute to its antitumor effects. JNJ-17029259 delays the growth of a wide range of human tumor xenografts in nude mice when administered orally as single-agent therapy. Histological examination revealed that the tumors have evidence of reduced vascularity after treatment. In addition, JNJ-17029259 enhances the effects of the conventional chemotherapeutic drugs doxorubicin and paclitaxel in xenograft models when administered orally in combination therapy. An orally available angiogenesis inhibitor that can be used in conjunction with standard chemotherapeutic agents to augment their activity may have therapeutic benefit in stopping the progression of cancer and preventing metastasis.