RRC ID 43235
Author Taguchi E, Nakamura K, Miura T, Shibuya M, Isoe T.
Title Anti-tumor activity and tumor vessel normalization by the vascular endothelial growth factor receptor tyrosine kinase inhibitor KRN951 in a rat peritoneal disseminated tumor model.
Journal Cancer Sci.
Abstract We assessed the antitumor efficacy of KRN951, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptors, using a rat colon cancer RCN-9 syngeneic model in which the tumor cells are transplanted into the peritoneal cavity of F344 rats. KRN951 treatments that commenced 4 days after tumor transplantation (day 4) significantly inhibited tumor-induced angiogenesis, the formation of tumor nodules in the mesenteric windows, and the accumulation of malignant ascites. Moreover, KRN951 treatments initiated on day 14, by which time angiogenesis and malignant ascites have already been well established, resulted in the regression of newly formed tumor vasculatures with aberrant structures and also in the apparent loss of malignant ascites by the end of the study period. Quantitative analysis of the vessel architecture on mesenteric windows revealed that KRN951 not only regressed, but also normalized the tumor-induced neovasculature. Continuous daily treatments with KRN951 significantly prolonged the survival of rats bearing both early stage and more advanced-stage tumors, compared with the vehicle-treated animals. The results of our current study thus show that KRN951 inhibits colon carcinoma progression in the peritoneal cavity by blocking tumor angiogenesis, ascites formation, and tumor spread, thereby prolonging survival. Moreover, these studies clearly demonstrate the therapeutic effects of KRN951 against established tumors in the peritoneal cavity, including the regression and normalization of the tumor neovasculature. Our findings therefore suggest that KRN951 has significant potential as a future therapeutic agent in the treatment of peritoneal cancers with ascites.
Volume 99(3)
Pages 623-30
Published 2008-3
DOI 10.1111/j.1349-7006.2007.00724.x
PMID 18201272
MeSH Animals Antineoplastic Agents / therapeutic use* Ascites / metabolism Cell Line, Tumor Colonic Neoplasms / pathology Disease Models, Animal Humans Isoxazoles / therapeutic use* Neovascularization, Pathologic / drug therapy Peritoneal Neoplasms / blood supply Peritoneal Neoplasms / drug therapy* Peritoneal Neoplasms / secondary* Phenylurea Compounds / therapeutic use* Phosphorylation Protein Kinase Inhibitors / therapeutic use* Rats Rats, Inbred F344 Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors*
IF 4.372
Times Cited 22
Human and Animal Cells