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¹ Department of Oncological and Regenerative Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Kuramoto, Tokushima and ² Shionogi Research Laboratories, Shionogi and Co., Ltd., Fukushima, Osaka, Japan

Requests for reprints: Kazuya Kondo, Department of Oncological and Regenerative Surgery, School of Medicine, University of Tokushima, Kuramoto-cho, Tokushima 770-8503, Japan. Phone: 81-88-633-7143; Fax: 81-88-633-7144. E-mail: kondo{at}clin.med.tokushima-u.ac.jp

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.

Received 1/31/05; revised 6/21/05; accepted 7/15/05.

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