In vivo antitumor activity of the NF-kappaB inhibitor dehydroxymethylepoxyquinomicin in a mouse model of adult T-cell leukemia.

Abstract

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-kappaB, is induced by HTLV-I and is central to the ensuing neoplasia. To examine the effect of a novel NF-kappaB 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.

• Authors: Takeo Ohsugi, Ryouichi Horie, Toshio Kumasaka, Akira Ishida, Takaomi Ishida, Kazunari Yamaguchi, Toshiki Watanabe, Kazuo Umezawa, Toru Urano
• Journal: Carcinogenesis (Carcinogenesis) Vol. 26 Issue 8 Pg. 1382-8 (Aug 2005) ISSN: 0143-3334 [Print] England
• PMID: 15831528 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzamides
• Cyclohexanones
• NF-kappa B
• dehydroxymethylepoxyquinomicin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Base Sequence
• Benzamides (pharmacology)
• Binding Sites
• Cell Division (drug effects)
• Cell Line, Tumor
• Consensus Sequence
• Cyclohexanones (pharmacology)
• Disease Models, Animal
• Human T-lymphotropic virus 1 (drug effects, physiology)
• Humans
• Leukemia-Lymphoma, Adult T-Cell (drug therapy, pathology)
• Mice
• NF-kappa B (antagonists & inhibitors, metabolism)
• Transplantation, Heterologous