title: The kringle domain of tissue-type plasminogen activator inhibits in vivo tumor growth.
abstract: The two-kringle domain of tissue-type plasminogen activator (t-PA) has previously been shown to contain anti-angiogenesis activity. In this study, we explored the potential in vivo anti-tumor effects of the recombinant kringle domain (TK1-2) of human t-PA. Anti-tumor effects of purified Pichia-driven TK1-2 were examined in nude mice models by subcutaneous implantation of human lung (A-549) and colon (DLD-1, HCT-116) cancer cell lines. Mice bearing the tumors were injected with PBS or purified TK1-2 (30 mg/kg) i.p. every day for 22 days. TK1-2 treatment suppressed the A-549, DLD-1, and HCT-116 tumor growth by 85.3%, 52.4%, and 62.5%, respectively. Immunohistological examination of the tumor tissues showed that TK1-2 treatment decreased the vessel density and also the expression of angiogenesis-related factors including angiogenin, VEGF, alpha-SMA, vWF, and TNF-alpha, and increased the apoptotic fraction of cells. TK1-2 neither inhibited in vitro growth of these cancer cells nor affected t-PA-mediated fibrin clot lysis. These results suggest that TK1-2 inhibits the tumor growth by suppression of angiogenesis without interfering with fibrinolysis.
authors.affiliation: Cancer Research Institute, Catholic Research Institutes of Medical Sciences, The Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors.forename: Byoung-Shik
authors.initials: BS
authors.lastname: Shim
authors.forename: Byoung-Hak
authors.initials: BH
authors.lastname: Kang
authors.forename: Yong-Kil
authors.initials: YK
authors.lastname: Hong
authors.forename: Hyun-Kyung
authors.initials: HK
authors.lastname: Kim
authors.forename: Il-Ha
authors.initials: IH
authors.lastname: Lee
authors.forename: Soo-Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Lee
authors.forename: Suk-Keun
authors.initials: SK
authors.lastname: Lee
authors.forename: Young Ae
authors.initials: YA
authors.lastname: Joe
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005337:Fibrin / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018082:Kringles; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D010959:Tissue Plasminogen Activator / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D042501:Angiogenic Proteins; D005337:Fibrin; D010959:Tissue Plasminogen Activator