title: A new ATL xenograft model and evaluation of pyrrolidine dithiocarbamate as a potential ATL therapeutic agent.
abstract: Adult T-cell leukemia/lymphoma (ATL) is caused by human T-lymphotrophic virus type 1 infection and is one of the most refractory malignant T-cell lymphomas. Improvement of ATL therapy options requires the establishment of appropriate ATL animal models. In this study, we successfully generated an ATL mouse model by xenotransplantation of primary peripheral blood mononuclear cells (PBMCs) isolated from ATL patients (ATL cells) into nonobese diabetic/severe combined immunodeficiency/Jak3-null mice (NOJ mice). To generate the model, the ATL S1T cell line was subcutaneously injected into mice. Primary ATL cells were then transplanted subcutaneously, intraperitoneally, or intravenously. ATL cells infiltrated multiple organs, and elevated human soluble interleukin 2 receptor (IL-2R) levels were detected in peripheral blood. Injection of one million primary ATL cells was needed for successful engraftment into host mice. Thawed cells, frozen long-term in liquid nitrogen, could also be transplanted; however, more cells were required to achieve similar results. The median mouse survival time was proportional to the number of cells injected. Successful secondary transplantation of ATL cells from one NOJ mouse into another was achieved and confirmed by T-cell receptor analysis. Finally, we examined the effects of the antioxide pyrrolidine dithiocarbamate (PDTC) as an antitumor agent in vivo. PDTC administration inhibited the increase of soluble IL-2R and improved mouse survival, suggesting that this compound has potential as an anti-ATL agent. We demonstrated that ATL cells could be stably xenotransplanted into NOJ mice using primary cells. This model will be useful in the establishment of novel therapies to treat ATL.
authors.affiliation: Division of Hematology and Immunology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences of Kagoshima University, Kagoshima, Japan; Department of Hematology and Immunology, Kagoshima University Hospital, Kagoshima, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakamura
authors.affiliation: Division of Hematology and Immunology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences of Kagoshima University, Kagoshima, Japan; Department of Hematology and Immunology, Kagoshima University Hospital, Kagoshima, Japan. Electronic address: myoshimi@m.kufm.kagoshima-u.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yoshimitsu
authors.affiliation: Division of Hematology and Immunology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences of Kagoshima University, Kagoshima, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Kuroki
authors.affiliation: Division of Hematology and Immunology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences of Kagoshima University, Kagoshima, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Hachiman
authors.affiliation: Division of Hematology and Immunology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences of Kagoshima University, Kagoshima, Japan; Department of Hematology and Immunology, Kagoshima University Hospital, Kagoshima, Japan.
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Kamada
authors.affiliation: Division of Hematology and Immunology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences of Kagoshima University, Kagoshima, Japan.
authors.forename: Chibueze C
authors.initials: CC
authors.lastname: Ezinne
authors.affiliation: Division of Hematology and Immunology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences of Kagoshima University, Kagoshima, Japan; Department of Hematology and Immunology, Kagoshima University Hospital, Kagoshima, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Arai
authors.affiliation: Department of Hematology and Immunology, Kagoshima University Hospital, Kagoshima, Japan.
authors.forename: Hirosaka
authors.initials: H
authors.lastname: Inoue
authors.affiliation: Department of Hematology and Immunology, Kagoshima University Hospital, Kagoshima, Japan.
authors.forename: Heiichirou
authors.initials: H
authors.lastname: Hamada
authors.affiliation: Department of Hematology and Immunology, Kagoshima University Hospital, Kagoshima, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Hayashida
authors.affiliation: Division of Hematology and Immunology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences of Kagoshima University, Kagoshima, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Department of Hematology and Immunology, Kagoshima University Hospital, Kagoshima, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fujino
authors.affiliation: Department of Hematology and Immunology, Kagoshima University Hospital, Kagoshima, Japan.
authors.forename: Naosuke
authors.initials: N
authors.lastname: Arima
authors.affiliation: Department of Hematology and Immunology, Kagoshima University Hospital, Kagoshima, Japan.
authors.forename: Mamiko
authors.initials: M
authors.lastname: Arima
authors.affiliation: Department of Hematology and Immunology, Kagoshima University Hospital, Kagoshima, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Tabuchi
authors.affiliation: Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Okada
authors.affiliation: Division of Hematology and Immunology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences of Kagoshima University, Kagoshima, Japan; Department of Hematology and Immunology, Kagoshima University Hospital, Kagoshima, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Arima
mesh_terms: D000328:Adult; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D064593:Heterografts; D015368:Human T-lymphotropic virus 1; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009368:Neoplasm Transplantation; D011759:Pyrrolidines / Q000494:pharmacology*; D013859:Thiocarbamates / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D000975:Antioxidants; D011759:Pyrrolidines; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid