title: Direct effect of dasatinib on proliferation and cytotoxicity of natural killer cells in in vitro study.
abstract: Lymphocytosis predominantly due to natural killer (NK) cells has been reported in nearly a half of chronic myelogenous leukemia (CML) patients who were being treated with dasatinib. Besides, dasatinib-treated patients with lymphocytosis have a better prognosis than patients without lymphocytosis. In order to elucidate the effects of dasatinib on the proliferation of lymphocyte subset, dasatinib was added to the culture of peripheral blood mononuclear cells with IL-2 (lymphokine-activated killer culture) or a low dose of IL-2 with zoledronate (γδ T-cell culture). In both culture conditions, NK cells were increased in both percentage and absolute number in the culture with dasatinib compared with control culture without dasatinib. The increase of NK cells was dose dependent of dasatinib in the range of 2-25 nM. NK cell cytotoxicity of cultured cells with dasatinib was demonstrated to be superior to control cells without dasatinib in cytotoxicity assay using EGFP-transfected K562 cells as target cells. The present study suggested that lymphocytosis in dasatinib-treated CML patients is at least partly associated with a direct effect of dasatinib to stimulate the proliferation of NK cells. Favourable prognosis in patients with dasatinib-induced lymphocytosis might be associated with the effects of dasatinib to potentiate NK cytotoxicity in vivo.
authors.affiliation: Laboratory of Hematology and Oncology, Graduate School of Health Sciences, Niigata University, Niigata, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Uchiyama
authors.forename: Naoya
authors.initials: N
authors.lastname: Sato
authors.forename: Miwako
authors.initials: M
authors.lastname: Narita
authors.forename: Akie
authors.initials: A
authors.lastname: Yamahira
authors.forename: Minami
authors.initials: M
authors.lastname: Iwabuchi
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Furukawa
authors.forename: Hirohito
authors.initials: H
authors.lastname: Sone
authors.forename: Masuhiro
authors.initials: M
authors.lastname: Takahashi
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D000069439:Dasatinib; D004164:Diphosphonates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000188:drug therapy; D008218:Lymphocytosis / Q000139:chemically induced; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D011743:Pyrimidines / Q000009:adverse effects / Q000494:pharmacology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis; D013268:Stimulation, Chemical; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D013844:Thiazoles / Q000009:adverse effects / Q000494:pharmacology*; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D007093:Imidazoles; D007376:Interleukin-2; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D016692:Receptors, Antigen, T-Cell, gamma-delta; D013844:Thiazoles; D000077211:Zoledronic Acid; D000069439:Dasatinib
keywords: NK cells; cytotoxicity; dasatinib; proliferation