Downregulation of matrix metalloprotease-9 and urokinase plasminogen activator by TX-1877 results in decreased tumor growth and metastasis on xenograft model of rectal cancer.

Author(s): Miyake K, Shimada M, Nishioka M, Sugimoto K, Batmunkh E, Uto Y, Nagasawa H, Hori H

Affiliation(s): Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan. kota166@clin.med.tokushima-u.ac.jp

Publication date & source: 2009-10, Cancer Chemother Pharmacol., 64(5):885-92. Epub 2009 Feb 12.

Publication type: Research Support, Non-U.S. Gov't

PURPOSE: It is well known that hypoxic milieu is the primary cancer environment. Therefore, tumor hypoxia is considered to be a potential therapeutic target. In the present study, we investigated the antitumor and antimetastatic effect of hypoxic cell radiosensitizer, TX-1877 on xenograft model of rectal cancer. METHODS: Nude mice bearing subcutaneously or orthotopically implanted human colon cancer cell lines HCT-116 and HT-29 were treated with TX-1877, irradiation or TX-1877 with irradiation. Tumor volume, survival, expression of matrix metalloproteinase (MMP)-2, MMP-7, MMP-9 and urokinase-type plasminogen activator (uPA) and incidence of lymph node metastasis were evaluated in treatment versus control group. RESULTS: In subcutaneous model, tumor treated with TX-1877 and irradiation showed significant reductions in volume (P < 0.05 vs. control, TX-1877 or irradiation group). Quantitative real-time reverse transcription-PCR and immunohistochemical analysis revealed that TX-1877 significantly inhibited expression of the MMP-9 and uPA. These treatments also inhibited the para-aortic lymph node metastasis, however, did not prolong the survival in orthotopic model. CONCLUSIONS: These data show that the treatment of TX-1877 with irradiation decreased growth of human rectal cancer and, furthermore, suppressed lymph node metastasis.