A novel matrix metalloproteinase inhibitor, FYK-1388 suppresses tumor growth, metastasis and angiogenesis by human fibrosarcoma cell line.
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.
Shinoda
Kinya
K
Department of Internal Medicine IV, Nippon Medical School, Tokyo 113-8603, Japan.
Shibuya
Masahiko
M
Hibino
Suguru
S
Ono
Yasushi
Y
Matsuda
Kuniko
K
Takemura
Akira
A
Zou
Datong
D
Kokubo
Yutaka
Y
Takechi
Akiko
A
Kudoh
Shoji
S
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
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; C476604:FYK 1388; D006146:Guanidines; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D009363:Neoplasm Proteins; D011480:Protease Inhibitors