Carcinogenesis Advance Access originally published online on April 14, 2005
Carcinogenesis 2005 26(8):1382-1388; doi:10.1093/carcin/bgi095
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Carcinogenesis vol.26 no.8 © Oxford University Press 2005; all rights reserved.
In vivo antitumor activity of the NF-
B inhibitor dehydroxymethylepoxyquinomicin in a mouse model of adult T-cell leukemia
Division of Microbiology and Genetics, Center for Animal Resources and Development, Institute of Resource Development and Analysis, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan, 1 Department of Hematology, Faculty of Medicine, Kitasato University, 1-15-1 Sagamihara, Kanagawa 228-8555, Japan, 2 Department of Pathology (I), Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan, 3 Department of Computer and Media Science, Faculty of Engineering, Yamanashi University, 4-3-11 Takeda, Kofu, Yamanashi 400-8511, Japan, 4 Division of Pathology, Department of Cancer Research, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan, 5 Department of Safety Research on Blood and Biologics, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashimurayama-shi, Tokyo 208-0011, Japan and 6 Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-0061, Japan
* To whom correspondence should be addressed. Tel: +81 96 373 6549; Fax: +81 96 373 6552; Email: ohsugi{at}gpo.kumamoto-u.ac.jp
Adult T-cell leukemia (ATL) is an aggressive neoplasm caused by human T-cell leukemia virus type I (HTLV-I). The nuclear transcription factor, NF-
B, is induced by HTLV-I and is central to the ensuing neoplasia. To examine the effect of a novel NF-B inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on ATL in vivo, we developed an improved severe combined immunodeficiency (SCID) mouse model for ATL. Five-week-old SCID mice in which natural killer (NK) cell activity had been eliminated were inoculated intraperitoneally with the HTLV-I-infected cell lines, TL-Om1, MT-1, MT-2 and HUT-102. No engraftment of TL-Om1 cells and little tumorigenesis of MT-1 cells were detected 40 days after injection. In contrast, inoculation of mice with MT-2 and HUT-102 cells elicited high mortality, 100% frequency of gross tumor formation and tumor cell infiltration of various organs, all of which were reduced by coadministration of DHMEQ during the inoculation. Moreover, tumors from mice treated with DHMEQ had a high frequency of apoptosis. These results suggest that DHMEQ induces apoptosis in HTLV-I-transformed cells in vivo, resulting in inhibition of tumor formation and organ infiltration, thereby enhancing survival.
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