title: Anti-adult T-cell leukemia effects of a novel synthetic retinoid, Am80 (Tamibarotene).
abstract: Clinical trials for treatment of adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type I (HTLV-I) using all-trans-retinoic acid (ATRA) have shown satisfactory therapeutic responses, although efficacies were limited. Recently, many synthetic retinoids have been developed and among them, a novel synthetic retinoid, Am80 (Tamibarotene) is an RARalpha- and RARbeta-specific retinoid expected to overcome ATRA resistance. The present study examined the inhibitory effects of Am80 on HTLV-I-infected T-cell lines and ATL cells. Am80 had negligible growth inhibition of peripheral blood mononuclear cells but marked growth inhibition of both HTLV-I-infected T-cell lines and ATL cells. Am80 arrested cells in the G1 phase of the cell cycle and induced apoptosis in HTLV-I-infected T-cell lines. It inhibited also the phosphorylation of IkappaBalpha and NF-kappaB-DNA binding, in conjunction with reduction of expression of proteins involved in the G1/S cell cycle transition and apoptosis. Am80 also inhibited the expression of JunD, resulting in suppression of AP-1-DNA binding. Furthermore, severe combined immunodeficient mice with tumors induced by subcutaneous inoculation of HTLV-I-infected T cells, responded to Am80 treatment with partial regression of tumors and no side-effects. These findings demonstrate that Am80 is a potential inhibitor of NF-kappaB and AP-1, and is a potentially useful therapeutic agent against ATL.
authors.affiliation: Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Nakazato
authors.forename: Taeko
authors.initials: T
authors.lastname: Okudaira
authors.forename: Chie
authors.initials: C
authors.lastname: Ishikawa
authors.forename: Shinji
authors.initials: S
authors.lastname: Nakama
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sawada
authors.forename: Mariko
authors.initials: M
authors.lastname: Tomita
authors.forename: Jun-nosuke
authors.initials: JN
authors.lastname: Uchihara
authors.forename: Naoya
authors.initials: N
authors.lastname: Taira
authors.forename: Masato
authors.initials: M
authors.lastname: Masuda
authors.forename: Yuetsu
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Kazuiku
authors.initials: K
authors.lastname: Ohshiro
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takasu
authors.forename: Naoki
authors.initials: N
authors.lastname: Mori
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001565:Benzoates / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle; D002455:Cell Division; D045744:Cell Line, Tumor; D005260:Female; D015368:Human T-lymphotropic virus 1 / Q000472:pathogenicity; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D013764:Tetrahydronaphthalenes / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D001565:Benzoates; D013764:Tetrahydronaphthalenes; C061133:tamibarotene
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