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

Katori, Hideaki; Baba, Yoshifumi; Imagawa, Yukari; Nishimura, Goshi; Kagesato, Yuumi; Takagi, Emi; Ishii, Akiko; Yanoma, Shunsuke; Maekawa, Ryuji; Yoshioka, Takayuki; Nagashima, Yoji; Kato, Yukio; Tsukuda, Mamoru

doi:10.1016/s0304-3835(01)00837-0

Cited by 29 publications

(12 citation statements)

References 25 publications

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“…Therefore, the development of selective inhibitors for tumor progression-associated MMPs, although sparing selected MMPs the activity of which is either beneficial to the host or that, if inhibited, produces side effects, is likely to offer additional therapeutic possibilities. In that context, more specific MMPIs such as , BPHA (21), MMI-166 (22) or ONO-4817 (23) have been developed. Pyrimidine-2,4,6-triones (barbiturates) are drugs used for decades as sedatives, narcotics, and antiepileptic agents.…”

Section: Introductionmentioning

confidence: 99%

Anti-Invasive, Antitumoral, and Antiangiogenic Efficacy of a Pyrimidine-2,4,6-trione Derivative, an Orally Active and Selective Matrix Metalloproteinases Inhibitor

Maquoi

Sounni

Devy

et al. 2004

Clinical Cancer Research

151

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Section: Introductionmentioning

confidence: 99%

Anti-Invasive, Antitumoral, and Antiangiogenic Efficacy of a Pyrimidine-2,4,6-trione Derivative, an Orally Active and Selective Matrix Metalloproteinases Inhibitor

Maquoi

Sounni

Devy

et al. 2004

Clinical Cancer Research

151

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“…Matrix metalloproteinase inhibitor-166 inhibits matrix metalloproteinase-2, -9, and -14. 22,23 In this study, we compare matrix metalloproteinase-2 expression in cutaneous squamous cell carcinoma specimens representing precancerous (actinic keratosis), in situ, locally invasive, recurrent, and metastatic disease. Our goal is to examine for the presence of a correlation between the degree of matrix metalloproteinase-2 expression and tumor aggressiveness.…”

mentioning

confidence: 99%

Metalloproteinase-2 expression correlates with aggressiveness of cutaneous squamous cell carcinomas

2004

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Matrix metalloproteinases compose a family of enzymes involved in degradation of the extracellular matrix. Tumor cells must penetrate the basement membrane and traverse the extracellular matrix in order to invade surrounding structures and metastasize to distant sites. Gelatinases, particularly gelatinase A (matrix metalloproteinase-2), demonstrate degradative activity against components of the basement membrane and may be involved in the progression of in situ squamous cell carcinoma lesions. Matrix metalloproteinase-2 overexpression has been correlated with tumor invasiveness and metastasis in a wide variety of cancer types, including squamous cell carcinoma arising on mucous membranes. However, correlation between matrix metalloproteinase-2 overexpression and the spread and prognosis of cutaneous squamous cell carcinoma has not been characterized in the literature at present. In this study, we used immunohistochemical techniques to examine the expression of matrix metalloproteinase-2 in 10 actinic keratosis, 15 in situ, 13 invasive, 13 primary (with documented metastatic disease), 11 metastatic, and 8 recurrent squamous cell carcinoma cases. We found that while the average staining intensity (scale 0-3 þ , 3 þ being strongest) of actinic keratosis and in situ lesions was not statistically significant (0.87-1.3 and 0.75-1.4, respectively), the average staining intensity of invasive squamous cell carcinomas (1.6-2.5) was significantly greater than that of actinic keratosis and in situ lesions. Likewise, while the average staining intensity of primary squamous cell carcinomas and metastatic squamous cell carcinomas was not found to be statistically significant (3.1-3.5 and 3.1-3.8, respectively), the average staining intensity of these lesions was significantly higher than that of invasive lesions. We also found that the intensity of matrix metalloproteinase-2 staining correlates with cellular atypia, inflammation, neovascularization, and the invasive tumor front, as well as tumor aggressiveness, and may play a role in the pathogenesis, invasion, and metastasis of cutaneous squamous cell carcinoma.

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“…Some studies have reported that lymph node metastasis in lung cancer closely correlated with the activation of MMP-2 and MT1-MMP, which are specific activators of MMP-2 on the cell surface (5,6). We speculated that MMI-166 with the inhibitory potential of MMP-2 activity contributes to the suppression of mediastinal lymph node metastasis in lung cancer, whereas previous reports show that MMI-166 inhibits tumor angiogenesis (22,23). The mechanism inhibiting lymph node metastasis in this study may include both the suppression of extracellular matrix degradation and the inhibition of angiogenesis at metastatic sites.…”

Section: Discussionmentioning

confidence: 70%

“…There are several classes of agents which target the different steps involved in angiogenesis (21). These include (a) drugs inhibiting MMP, (b) drugs that block endothelial cell signaling by vascular endothelial growth factor and its receptor, (c) drugs that are similar to (22,23). This study also showed that the Ma44-3 lung cancer cell line moderately expressed both MMP-9 and MMP-2, and that 200 mg/kg body weight of MMI-166 significantly suppressed the Mediastinal metastatic lesions in the control group showed gelatinolytic activity on GN film, whereas mediastinal metastasis in the MMP-166 group showed no activity on GN film.…”

Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinase inhibitor MMI-166 inhibits lymphogenous metastasis in an orthotopically implanted model of lung cancer

Fujino¹,

Kondo²,

Ishikura³

et al. 2005

Molecular Cancer Therapeutics

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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 F 0.009 versus MMI-166, 0.069 F 0.008 mg; P = 0.005; metastatic area: control, 93,495 F 55,747 versus MMI-166, 22,747 F 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. [Mol Cancer Ther 2005; 4(9):1409 -16]

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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

Cited by 29 publications

References 25 publications

Anti-Invasive, Antitumoral, and Antiangiogenic Efficacy of a Pyrimidine-2,4,6-trione Derivative, an Orally Active and Selective Matrix Metalloproteinases Inhibitor

Anti-Invasive, Antitumoral, and Antiangiogenic Efficacy of a Pyrimidine-2,4,6-trione Derivative, an Orally Active and Selective Matrix Metalloproteinases Inhibitor

Metalloproteinase-2 expression correlates with aggressiveness of cutaneous squamous cell carcinomas

Matrix metalloproteinase inhibitor MMI-166 inhibits lymphogenous metastasis in an orthotopically implanted model of lung cancer

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