title: Bimodal anti-glioma mechanisms of cilengitide demonstrated by novel invasive glioma models.
abstract: Integrins are expressed in tumor cells and tumor endothelial cells, and likely play important roles in glioma angiogenesis and invasion. We investigated the anti-glioma mechanisms of cilengitide (EMD121974), an αvβ3 integrin inhibitor, utilizing the novel invasive glioma models, J3T-1 and J3T-2. Immunohistochemical staining of cells in culture and brain tumors in rats revealed positive αvβ3 integrin expression in J3T-2 cells and tumor endothelial cells, but not in J3T-1 cells. Established J3T-1 and J3T-2 orthotopic gliomas in athymic rats were treated with cilengitide or solvent. J3T-1 gliomas showed perivascular tumor cluster formation and angiogenesis, while J3T-2 gliomas showed diffuse single-cell infiltration without obvious angiogenesis. Cilengitide treatment resulted in a significantly decreased diameter of the J3T-1 tumor vessel clusters and its core vessels when compared with controls, while an anti-invasive effect was shown in the J3T-2 glioma with a significant reduction of diffuse cell infiltration around the tumor center. The survival of cilengitide-treated mice harboring J3T-1 tumors was significantly longer than that of control animals (median survival: 57.5 days and 31.8 days, respectively, P < 0.005), while cilengitide had no effect on the survival of mice with J3T-2 tumors (median survival: 48.9 days and 48.5, P = 0.69). Our results indicate that cilengitide exerts a phenotypic anti-tumor effect by inhibiting angiogenesis and glioma cell invasion. These two mechanisms are clearly shown by the experimental treatment of two different animal invasive glioma models.
authors.affiliation: Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Onishi
authors.forename: Tomotsugu
authors.initials: T
authors.lastname: Ichikawa
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kurozumi
authors.forename: Kentaro
authors.initials: K
authors.lastname: Fujii
authors.forename: Koichi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Michiue
authors.forename: E Antonio
authors.initials: EA
authors.lastname: Chiocca
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
authors.forename: Isao
authors.initials: I
authors.lastname: Date
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D004195:Disease Models, Animal; D004285:Dogs; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D011923:Rats, Nude; D012910:Snake Venoms / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D012910:Snake Venoms; C422910:Cilengitide