Therapeutic Benefit of a Dissociated Glucocorticoid and the Relevance of In Vitro Separation of Transrepression from Transactivation Activity
| Autor: | Jane E. Redford, Clifford H. Battram, Stephen E. Bottoms, Sharon Wicks, Martyn Foster, Paul Woodman, Stephen E Webber, Thomas J. Brown, Maria G. Belvisi |
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| Rok vydání: | 2001 |
| Předmět: |
Male
Transcriptional Activation medicine.medical_specialty Hydroxycorticosteroids Prednisolone medicine.medical_treatment Osteocalcin Immunology Anti-Inflammatory Agents Administration Oral Pulmonary Edema Pharmacology Bone remodeling Steroid Rats Sprague-Dawley Transactivation Therapeutic index In vivo Internal medicine Intubation Intratracheal medicine Animals Desoximetasone Immunology and Allergy Growth Plate Budesonide Glucocorticoids Transrepression Chemistry Dextrans Femur Head In vitro Rats Bone Diseases Metabolic Endocrinology Gene Expression Regulation Immunosuppressive Agents hormones hormone substitutes and hormone antagonists Glucocorticoid medicine.drug |
| Zdroj: | The Journal of Immunology. 166:1975-1982 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | Glucocorticoids (GCs) are the mainstay of asthma therapy; however, major side effects limit their therapeutic use. GCs influence the expression of genes either by transactivation or transrepression. The antiinflammatory effects of steroids are thought to be due to transrepression and the side effects, transactivation. Recently, a compound, RU 24858, has been identified that demonstrated dissociation between transactivation and transrepression in vitro. RU 24858 exerts strong AP-1 inhibition (transrepression), but little or no transactivation. We investigated whether this improved in vitro profile results in the maintenance of antiinflammatory activity (evaluated in the Sephadex model of lung edema) with reduced systemic toxicity (evaluated by loss in body weight, thymus involution, and bone turnover) compared with standard GCs. RU 24858 exhibits comparable antiinflammatory activity to the standard steroid, budesonide. However, the systemic changes observed indicate that transactivation events do occur with this GC with similar potency to the standard steroids. In addition, the GCs profiled showed no differentiation on quantitative osteopenia of the femur. These results suggest that in vitro separation of transrepression from transactivation activity does not translate to an increased therapeutic ratio for GCs in vivo or that adverse effects are a consequence of transrepression. |
| Databáze: | OpenAIRE |
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