title: Sunitinib suppresses tumor growth and metastases in a highly metastatic mouse mammary cancer model.
abstract: BACKGROUND
  Sunitinib is an inhibitor that blocks tyrosine phosphorylation (p-Tyr) of receptors including vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor. Sunitinib suppresses angiogenesis and cell proliferation and is an effective treatment for renal cell carcinoma and gastrointestinal stromal tumors. In the present study, we examined the antitumor and antimetastatic activities of sunitinib in mouse metastatic mammary cancer.
  
  
  METHODS
  Mammary tumors induced by inoculation of BJMC3879 cells into mice were treated with sunitinib using mini-osmotic pumps. At 1 week and 7 weeks after initiation of drug administration, cancer tissue was removed and carried out histopathological and immunohistochemical examination.
  
  
  RESULTS
  Tumor growth, as well as metastasis to the lungs and other organs, was significantly inhibited in sunitinib-treated mice. Cell death areas in mammary carcinomas were much larger in the sunitinib-treated groups than in the control group. In addition, sunitinib induced necrotic cell death rather than apoptosis. Although microvessel density was significantly lower in the sunitinib-treated mammary tumors, numbers of metastases to lymph nodes and the number of lymphatic vessels in the mammary tumors were not significantly different among groups. Cell proliferation, as assessed by BrdU-labeling indices, was significantly lower in mammary carcinomas of sunitinib-treated mice. The amounts of p-VEGFR-2 and p-Tyr, as determined by immunohistochemistry, were greatly reduced in sunitinib-treated mice.
  
  
  CONCLUSIONS
  In a mouse model of mammary cancer, sunitinib inhibited tumor growth and metastasis (with the exception of lymph node metastasis), angiogenesis, and cell proliferation possibly due to reduced levels of p-VEGFR-2 and p-Tyr.
authors.affiliation: Department of Anatomy and Cell Biology, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Masa-Aki
authors.initials: MA
authors.lastname: Shibata
authors.forename: Junji
authors.initials: J
authors.lastname: Morimoto
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Otsuki
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007211:Indoles / Q000627:therapeutic use*; D008207:Lymphatic Metastasis; D042601:Lymphatic Vessels / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D011758:Pyrroles / Q000627:therapeutic use*; D000077210:Sunitinib; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; D014443:Tyrosine; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077210:Sunitinib