title: Matrix metalloproteinase inhibitor MMI-166 inhibits lymphogenous metastasis in an orthotopically implanted model of lung cancer.
abstract: Matrix metalloproteinases (MMP) are considered to be critically involved in tumor invasion and the metastasis of various cancers. MMI-166 is a selective inhibitor of matrix metalloproteinase (MMP-2, MMP-9, and MMP-14). The purpose of this study was to evaluate the effects of MMI-166 on both the growth of the implanted tumor and the lymph node metastasis of the mediastinum and prolonging the life span, using an orthotopic implantation model of the Ma44-3 cancer cell line. We examined the anti-invasive effect of MMI-166 in lung cancer cell lines using an in vitro invasion assay. Next, we examined the anticancer effect of MMI-166 in vivo. MMI-166 (200 mg/kg body weight) or a vehicle was administered orally to the orthotopically implanted lung cancer model. MMI-166 dose-dependently inhibited the invasion of cancer cell lines with expressions of MMP-2 and/or MMP-9 in vitro. In vivo, MMI-166 significantly inhibited mediastinal lymph node metastasis in this orthotopic model (weight of the mediastinum: control, 0.089 +/- 0.009 versus MMI-166, 0.069 +/- 0.008 mg; P = 0.005; metastatic area: control, 93,495 +/- 55,747 versus MMI-166, 22,747 +/- 17,478 pixels; P = 0.045). MMI-166 prolonged the life span by 6 days in median survival time in the orthotopically implanted model (P = 0.039). These results showed that MMI-166 could possibly inhibit lymph node metastasis and prolong the life span in lung cancer patients.
authors.affiliation: Department of Oncological and Regenerative Surgery, School of Medicine, University of Tokushima, Kuramoto-cho, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Fujino
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kondo
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ishikura
authors.forename: Hideo
authors.initials: H
authors.lastname: Maki
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Kinoshita
authors.forename: Takanori
authors.initials: T
authors.lastname: Miyoshi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Naruhiko
authors.initials: N
authors.lastname: Sawada
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Takizawa
authors.forename: Taeko
authors.initials: T
authors.lastname: Nagao
authors.forename: Shoji
authors.initials: S
authors.lastname: Sakiyama
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Monden
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply / Q000517:prevention & control* / Q000556:secondary*; D004195:Disease Models, Animal; D006801:Humans; D007279:Injections, Subcutaneous; D008175:Lung Neoplasms / Q000098:blood supply / Q000473:pathology*; D008207:Lymphatic Metastasis; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D013449:Sulfonamides / Q000494:pharmacology*; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; C419963:N-alpha-(4-(2-phenyl-2H- tetrazole-5-yl) phenyl sulfonyl)-D-tryptophan; D013449:Sulfonamides