title: Combination of HDAC inhibitor MS-275 and IL-2 increased anti-tumor effect in a melanoma model via activated cytotoxic T cells.
abstract: BACKGROUND
  Histone deacetylase (HDAC) inhibitors are immunomodulatory, and demonstrate antitumor activity in various tumor models including malignant melanoma.
  
  
  OBJECTIVE
  The present study examines the effectiveness of IL-2 and HDAC inhibitor MS-275-combination therapy in a murine melanoma model.
  
  
  METHODS
  B16F10 cells were implanted subcutaneously in C57BL/6 mice which were randomly divided into four groups and treated with either IL-2 by subcutaneous injection, MS-275 by oral gavage (5 days/week, daily for 2 weeks), or a combination of the two agents.
  
  
  RESULTS
  MS-275 treatment showed a dose-dependent inhibitory effect on B16 cells in a colonogenic assay. Flow cytometry analysis indicated that MS-275 induced G1 arrest but not apoptosis in vitro, but IL-2 failed to inhibit cell proliferation. The combination of MS-275 and IL-2 had a statistically significant additive inhibitory effect on melanoma tumor weight and volume in vivo. Significantly higher survival was evident in the combination group compared with the control or single-agent groups. The combination therapy produced a greater ratio of CD8(+) CD69(+) T cells in lymph nodes than was seen in the MS-275-treatment and no-treatment groups among tumoriferous mice. Splenocytes from mice treated with MS-275 and the combination therapy demonstrated greater lysis of melanoma cells in vitro than splenocytes from mice treated with IL-2 or those without treatment. A significant antitumor effect from IL-2 and MS-275-combination therapy in vivo was seen in the increased number of activated CD8(+) T cells.
  
  
  CONCLUSIONS
  These data provide a convincing rationale for considering the role of epigenetics in future treatments for malignant melanoma.
authors.affiliation: Department of Dermatology, Tokyo Medical University, Tokyo, Japan; Department of Dermatology, Tokyo Metropolitan Tama Medical Center, Tokyo, Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Department of Dermatology, Tokyo Medical University, Tokyo, Japan. Electronic address: y-kato@tokyo-med.ac.jp.
authors.forename: Ikuyo
authors.initials: I
authors.lastname: Yoshino
authors.affiliation: Department of Dermatology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Chizu
authors.initials: C
authors.lastname: Egusa
authors.affiliation: Department of Dermatology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Maeda
authors.affiliation: Department of Oncology, Roswell Park Cancer Center, New York, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pili
authors.affiliation: Department of Dermatology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Tsuboi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D007279:Injections, Subcutaneous; D007376:Interleukin-2 / Q000008:administration & dosage; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008810:Mice, Inbred C57BL; D011725:Pyridines / Q000008:administration & dosage; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology; D013997:Time Factors
chemical_list: D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D007376:Interleukin-2; D011725:Pyridines; C118739:entinostat
keywords: Activated CD8-positive T lymphocyte; Combination therapy; Histone deacetylase inhibitor; Interleukin-2; Melanoma