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.
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.
Taguchi
Eri
E
Development Research Laboratories, Kirin Pharma, 3 Miyahara, Takasaki, Gunma 370-1295, Japan. e-taguchi@kirin.co.jp
Nakamura
Kazuhide
K
Miura
Toru
T
Shibuya
Masabumi
M
Isoe
Toshiyuki
T
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001201:Ascites / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D007555:Isoxazoles / Q000627:therapeutic use*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010534:Peritoneal Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000556:secondary*; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D007555:Isoxazoles; C514994:N-(2-chloro-4-((6,7-dimethoxy-4-quinolyl)oxy)phenyl)-N'-(5-methyl-3-isoxazolyl)urea; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor