title: Novel method for selecting immunosuppressive histone deacetylase (HDAC) inhibitors with minimal thrombocytopenia.
abstract: Histone deacetylase (HDAC) inhibitors repress interleukin-2 (IL-2) gene expression in T cells and possess immunosuppressive activity in vivo. In addition to its immunosuppressive activity, HDAC inhibitors block GATA binding protein-1 (GATA-1) gene expression in megakaryocytes and elicit thrombocytopenia. In this report we state that for a given immunosuppressive dose of HDAC inhibitor, the ratio of GATA-1 reporter gene activity relative to IL-2 reporter gene assay (G/I ratio of measured IC(50)) can be predictive of a HDAC inhibitor's thrombocytopenic effect. This study utilized nine HDAC inhibitors at a minimal effective dose in a rat heterotopic cardiac transplantation model and the resultant G/I ratios and platelet depletion rates were highly correlated (r=0.933). These results indicate that calculation of G/I ratio can be a novel method for selecting immunosuppressive HDAC inhibitor having minimal thrombocytopenic effect which will benefit the search for new immunosuppressants of greater safety and efficacy.
authors.affiliation: Pharmacology Research Laboratories, Astellas Pharma Inc., Yodogawa-ku, Osaka, Japan. hideaki.mtsuoka@us.astellas.com
authors.forename: Hideaki
authors.initials: H
authors.lastname: Matsuoka
authors.forename: Takao
authors.initials: T
authors.lastname: Fujimura
authors.forename: Akira
authors.initials: A
authors.lastname: Unami
authors.forename: Toshiko
authors.initials: T
authors.lastname: Yamada
authors.forename: Takahisa
authors.initials: T
authors.lastname: Noto
authors.forename: Yoko
authors.initials: Y
authors.lastname: Takata
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yoshizawa
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mori
authors.forename: Ichiro
authors.initials: I
authors.lastname: Aramori
authors.forename: Seitaro
authors.initials: S
authors.lastname: Mutoh
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D050982:GATA1 Transcription Factor / Q000235:genetics; D017930:Genes, Reporter / Q000187:drug effects; D016027:Heart Transplantation / Q000276:immunology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D007376:Interleukin-2 / Q000235:genetics; D019169:Jurkat Cells; D008297:Male; D010957:Plasmids / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts; D013844:Thiazoles; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced*; D016042:Transplantation, Heterotopic / Q000276:immunology
chemical_list: D004791:Enzyme Inhibitors; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D056572:Histone Deacetylase Inhibitors; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue