The inhibitory effect of matrix metalloproteinase inhibitor ONO-4817 on lymph node metastasis in tongue carcinoma.
BACKGROUND
ONO-4817 is a novel matrix metalloproteinase (MMP) inhibitor which has a broad inhibitory spectrum for MMPs. We investigated the inhibitory effect of ONO-4817 on cervical lymph node metastasis of tongue carcinoma.


METHODS
HSC-3-M3, a cell line derived from human tongue carcinoma with high metastatic potential for lymph node, was used. The direct cytotoxicity of ONO-4817 was assessed by MTT assay and the gelatinolytic activity by gelatin zymography and film in situ zymography (FIZ). The inhibitory effect on lymph node metastasis was examined by orthotopic implantation model with nude mice.


RESULTS
ONO-4817 had no direct cyototoxicity on HSC-3-M3 cells. Gelatin zymography and FIZ demonstrated a suppression of MMP-9 activation and a marked inhibition of gelatinolysis. Additionally, a suppression of cervical lymph node metastasis was shown by therapeutic experiment.


CONCLUSIONS
The MMP inhibitor, ONO-4817, is a candidate for adjunctive therapy of cervical lymph node metastasis in tongue carcinoma.
Yamashita
Taku
T
Department of Otolaryngology, Keio University, School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
Fujii
Masato
M
Tomita
Toshiki
T
Ishiguro
Ryuichiro
R
Tashiro
Masatsugu
M
Tokumaru
Yutaka
Y
Imanishi
Yorihisa
Y
Kanke
Minoru
M
Ogawa
Kaoru
K
Kameyama
Kaori
K
Otani
Yoshihide
Y
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology / Q000556:secondary; D002455:Cell Division / Q000187:drug effects; D017364:Collagenases / Q000378:metabolism; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010647:Phenyl Ethers / Q000494:pharmacology*; D014062:Tongue Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D014407:Tumor Cells, Cultured; D015431:Weight Loss / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D004792:Enzyme Precursors; D061965:Matrix Metalloproteinase Inhibitors; C414368:N-hydroxy-5-ethoxymethyloxy-2-methyl-4-(4-phenoxybenzoyl)aminopentanamide; D010647:Phenyl Ethers; D017364:Collagenases; C120487:pro-matrix metalloproteinase 9; D020780:Matrix Metalloproteinase 9