title: Prevention of induced colitis in mice by the ras antagonist farnesylthiosalicylic acid.
abstract: BACKGROUND
  Ras proteins are crucial for cell differentiation and proliferation. Targeting Ras with farnesylthiosalicylic acid (FTS), a Ras antagonist, has been suggested as a therapeutic strategy in proliferative and inflammatory diseases.
  
  
  OBJECTIVE
  To examine the role of Ras and the therapeutic potential of FTS in experimental colitis.
  
  
  METHODS
  Colitis was induced in 26 mice by adding 2.5% dextran sodium sulfate to their drinking water for 7 days during which 12 study mice were treated with FTS and 14 control mice were given normal saline. Two additional controls included 10 naïve mice treated with FTS and 7 naïve non-treated mice. The animals were followed clinically and sacrificed after 7 days. Their colons were isolated for histological assessment and for measurement of myeloperoxidase activity (MPO), tumor necrosis factor-α(TNF-α), and interleukin-1β(Il-1β) levels. Ras and activated Ras expression was determined by immunoblotting assays. T cell populations in the colon and spleen were analyzed by flow-cytometry.
  
  
  RESULTS
  FTS induced a 2.1-fold reduction in activated Ras levels (P < 0.004). FTS-treated mice had lower disease activity scores (3.9 ± 1.7 vs. 7.5 ± 2.3, P < 0.001), and lower levels of MPO activity (1.65 ± 0.6 vs. 2.6 ± 0.8 units/g, P < 0.007), Il-1β (2.4 ± 3.6 vs. 24.3 ± 17.5 pg/mg, P < 0.01) and TNF-α (0.63 ± 0.5 vs. 1.9 ± 1 pg/mg, P < 0.04). FTS increased regulatory T cell population in the spleen (1.9 ± 0.4-fold, P < 0.04), and decreased effector T cell populations in the colon and spleen by 24 ± 3% (P < 0.03) and 27 ± 1% (P < 0.02), respectively. FTS had no remarkable side effects.
  
  
  CONCLUSIONS
  Ras is involved in the inflammatory processes of induced colitis in mice and its inhibition by FTS ameliorates the severity of the inflammation.
authors: Department of Pediatrics, Dana Children's Hospital, 6 Weizman St., 64239, Tel-Aviv, Israel. orotal@gmail.com
authors: Tal
authors: T
authors: Oron
authors: Galit
authors: G
authors: Elad-Sfadia
authors: Roni
authors: R
authors: Haklai
authors: Elizabeta
authors: E
authors: Aizman
authors: Eli
authors: E
authors: Brazowski
authors: Yoel
authors: Y
authors: Kloog
authors: Shimon
authors: S
authors: Reif
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003092:Colitis / Q000503:physiopathology* / Q000517:prevention & control*; D003106:Colon / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005204:Farnesol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D005434:Flow Cytometry; D053583:Interleukin-1beta / Q000032:analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D009924:Organ Culture Techniques; D012459:Salicylates / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D012459:Salicylates; D014409:Tumor Necrosis Factor-alpha; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D018631:ras Proteins