salicylates and Autoimmune-Diseases

Farnesylthiosalisylic acid (FTS) is a potent non-toxic anticancer drug that targets oncogenic and pathologically activated Ras. The mechanism of action of FTS is well understood. It interferes with the binding of activated Ras proteins to their escort chaperons and with Ras tethering to the plasma membrane. This agent has been evaluated successfully in phase II clinical trials of pancreatic and lung cancer patients. It is generally agreed that Ras proteins play an important role in cancer, but they also drive activation of the immune system. Therefore we hypothesized that inhibiting Ras might be beneficial in autoimmune and inflammatory conditions. Over the past decade we have extensively studied the effects of FTS in multiple animal models of such diseases. We were able to show potent anti-inflammatory properties of FTS in autoimmune disease models such as systemic lupus erythematous, antiphospholipd syndrome, Guillain-Barré syndrome, multiple sclerosis, and inflammatory bowel diseases. Its potential was also shown in type I and type II diabetes. Animal models of contact dermatitis, allergic inflammation, and proliferative nephritis were studied as well. We have also investigated the molecular mechanisms, signaling pathways, and inflammatory mediators underlying these conditions. In this review we summarize our (and others) published data, and conclude that FTS has great potential as a safe anti-inflammatory drug.

Topics: Animals; Anti-Inflammatory Agents; Autoimmune Diseases; Diabetes Mellitus, Type 2; Disease Models, Animal; Farnesol; Humans; Protein Binding; ras Proteins; Salicylates

Topics: Adrenal Cortex Hormones; Arthritis, Rheumatoid; Autoimmune Diseases; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Myasthenia Gravis; Pemphigoid Gestationis; Polyarteritis Nodosa; Pregnancy; Pregnancy Complications; Salicylates; Scleroderma, Systemic; Thrombocytopenia; Thyroid Diseases

Topics: Abnormalities, Drug-Induced; Acetaminophen; Adrenal Cortex Hormones; Autoimmune Diseases; Azathioprine; Female; Fetus; Humans; Immunosuppressive Agents; Indomethacin; Infant, Newborn; Pregnancy; Pregnancy Complications; Salicylates

Topics: Adrenal Cortex Hormones; Autoimmune Diseases; Azathioprine; Chlorambucil; Cyclophosphamide; Drug Therapy, Combination; Folic Acid Antagonists; Histamine H1 Antagonists; Humans; Immunosuppression Therapy; Mercaptopurine; Salicylates; Skin; Skin Diseases

Activation and proliferation of lymphocytes requires the active signal transducer Ras. Activation of lymphocytes, associated with autoimmunity, may therefore be modified by S-farnesylthiosalicylic acid (FTS), a synthetic substance that detaches Ras from the inner cell membrane and induces its rapid degradation. The MRL/lpr mouse is a genetic model of a generalized autoimmune disease sharing many features and organ pathology with systemic lupus erythematosus (SLE) and the primary antiphospholipid syndrome (APS). The objective of the present study was to examine the effect of FTS on laboratory and clinical pathology in the MRL/lpr mouse. Female MRL/lpr (n = 50) and MRL/++ control (n = 35) mice were treated intraperitoneally with either FTS (5 mg/kg/day) or saline between 6 and 18 weeks of age. The mice were weighed, tested for proteinuria and lymphadenopathy, lymphocyte proliferation, antibodies, grip strength and behaviour in an open field. FTS treatment resulted in a 50% decrease in splenocyte proliferation to ConA, LPS and a disease specific antigen, beta(2)-glycoprotein-I, and in a significant decrease in serum antibody levels against cardiolipin and dsDNA. Proteinuria and grip strength were normalized and lymphadenopathy and postmortem lymph node and spleen weights were significantly reduced in FTS treated MRL/lpr mice. These findings indicate that modulation of Ras activation has a significant impact on the MRL/lpr model and may represent a new therapeutic approach for the treatment of systemic autoimmune diseases such as SLE and APS.

Topics: Animals; Antiphospholipid Syndrome; Autoantibodies; Autoimmune Diseases; Farnesol; Female; In Vitro Techniques; Lupus Erythematosus, Systemic; Lymphatic Diseases; Lymphocyte Activation; Lymphocytes; Mice; Mice, Inbred MRL lpr; ras Proteins; Salicylates

Topics: Adult; Amoxicillin; Anti-Ulcer Agents; Autoimmune Diseases; Bismuth; Drug Therapy, Combination; Female; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; L-Lactate Dehydrogenase; Metronidazole; Omeprazole; Organometallic Compounds; Purpura, Thrombocytopenic, Idiopathic; Salicylates; Tetracycline

Topics: Adrenal Cortex Hormones; Autoimmune Diseases; Humans; Myocardial Infarction; Pericarditis; Salicylates; Syndrome

Topics: Acid-Base Equilibrium; Adrenal Cortex Hormones; Aminopyrine; Antineoplastic Agents; Arthritis, Rheumatoid; Autoimmune Diseases; Gold; Health Education; Home Care Services; Humans; Indenes; Indomethacin; Inflammation; Phenylbutazone; Pyrazoles; Quinolines; Rest; Salicylates

Topics: Adrenal Cortex Hormones; Antigen-Antibody Reactions; Antineoplastic Agents; Arthritis; Arthritis, Rheumatoid; Autoantibodies; Autoimmune Diseases; Drug Therapy; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Phenylbutazone; Salicylates; Toxicology