title: A novel matrix metalloproteinase inhibitor, FYK-1388 suppresses tumor growth, metastasis and angiogenesis by human fibrosarcoma cell line.
abstract: The matrix metalloproteinases (MMPs) are likely to contribute to tumor cell invasion, metastasis and angiogenesis. Several MMP inhibitors have been developed, recently and their anti-tumor efficacy is being evaluated in clinical trials. FYK-1388 is a novel broad MMP inhibitor which blocks the activity of MMP-1, -2, -3, -7, -9, -13 and -14 (MT-MMP-1). It is especially effective against MMP-2 and -9 more so than other MMP inhibitors such as Marimastat, Ro 32-3555 and D-2163. Here, we investigated the anti-tumor efficacy of FYK-1388 using the human fibrosarcoma cell line HT-1080. These cells produced MMP-2 and -9, which FYK-1388 inhibited at a dose of 10(-8) M. FYK-1388 at 0.2 mg/mouse/day significantly suppressed tumor growth when given by s.c. injection for 22 days, experimental lung metastasis after 5 days s.c. injection and also suppressed tumor-induced angiogenesis in the dorsal air sac assay after 7 days s.c. injection. In the MTT assay, FYK-1388 had no effect on the in vitro growth of HT-1080 cells. These results suggest that FYK-1388 possesses anti-tumor efficacy as a result of inhibiting angiogenesis through the suppression of MMP-2 and -9 activity.
authors.affiliation: Department of Internal Medicine IV, Nippon Medical School, Tokyo 113-8603, Japan.
authors.forename: Kinya
authors.initials: K
authors.lastname: Shinoda
authors.forename: Masahiko
authors.initials: M
authors.lastname: Shibuya
authors.forename: Suguru
authors.initials: S
authors.lastname: Hibino
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ono
authors.forename: Kuniko
authors.initials: K
authors.lastname: Matsuda
authors.forename: Akira
authors.initials: A
authors.lastname: Takemura
authors.forename: Datong
authors.initials: D
authors.lastname: Zou
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kokubo
authors.forename: Akiko
authors.initials: A
authors.lastname: Takechi
authors.forename: Shoji
authors.initials: S
authors.lastname: Kudoh
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005354:Fibrosarcoma / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control / Q000556:secondary; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D007279:Injections, Subcutaneous; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; C476604:FYK 1388; D006146:Guanidines; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D009363:Neoplasm Proteins; D011480:Protease Inhibitors