title: Reduction of in vivo tumor growth by MMI-166, a selective matrix metalloproteinase inhibitor, through inhibition of tumor angiogenesis in squamous cell carcinoma cell lines of head and neck.
abstract: Matrix metalloproteinases (MMPs) have been implicated in tumor invasion, metastasis, and angiogenesis. We have recently shown that MMI-166, a new orally active MMP inhibitor specific for MMP-2 and -9, suppressed experimental metastasis of Lewis lung cancer, C-H1 human colon cancer, and pancreatic cancer without affecting tumor growth in vitro. In the present study, we determined whether oral administration of MMI-166 reduces tumor growth not only in such tumors but also in squamous cell carcinoma of head and neck (SCCHN). MMI-166 inhibited both activity of MMP-2 and -9 without affecting steady state levels of their mRNAs in SCCHN. Interestingly, protein levels of MMP-2 and -9 from the cultures were drastically diminished by culturing with MMI-166. This was also observed in xenografts of MMI-166-administered mice. In addition, daily oral administration of MMI-166 (100mg/kg) inhibited local tumor growth accompanied by the reduction of blood vessel density and Ki-67-positivity and increase in terminal deoxynucleotidyl transferase-mediated cUDP nick-end labeling (TUNEL)-positivity. These results suggested that orally administered MMI-166 reduced in vivo tumor growth of SCCHN through inhibition of angiogenesis and induction of apoptosis accompanied by the reduction of MMP productions and activities. Therefore, MMI-166 seems to be useful for tumor dormancy therapy of SCCHN.
authors.affiliation: Department of Otolaryngology, Yokohama City University School of Medicine, 3-9 Fukuuna, Kanazawa-ku, Yokohama 236-0004, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Katori
authors.forename: Yuh
authors.initials: Y
authors.lastname: Baba
authors.forename: Yukari
authors.initials: Y
authors.lastname: Imagawa
authors.forename: Goshi
authors.initials: G
authors.lastname: Nishimura
authors.forename: Yuumi
authors.initials: Y
authors.lastname: Kagesato
authors.forename: Emi
authors.initials: E
authors.lastname: Takagi
authors.forename: Akiko
authors.initials: A
authors.lastname: Ishii
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Yanoma
authors.forename: Ryuji
authors.initials: R
authors.lastname: Maekawa
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshioka
authors.forename: Yoji
authors.initials: Y
authors.lastname: Nagashima
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Kato
authors.forename: Mamoru
authors.initials: M
authors.lastname: Tsukuda
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000098:blood supply* / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006258:Head and Neck Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; C419963:N-alpha-(4-(2-phenyl-2H- tetrazole-5-yl) phenyl sulfonyl)-D-tryptophan; D013449:Sulfonamides