title: Therapeutic benefit of a dissociated glucocorticoid and the relevance of in vitro separation of transrepression from transactivation activity.
abstract: 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.
authors.affiliation: Aventis Pharma Research & Development, Dagenham Research Centre, Dagenham, Essex, United Kingdom. m.belvisi@ic.ac.uk
authors.forename: M G
authors.initials: MG
authors.lastname: Belvisi
authors.forename: S L
authors.initials: SL
authors.lastname: Wicks
authors.forename: C H
authors.initials: CH
authors.lastname: Battram
authors.forename: S E
authors.initials: SE
authors.lastname: Bottoms
authors.forename: J E
authors.initials: JE
authors.lastname: Redford
authors.forename: P
authors.initials: P
authors.lastname: Woodman
authors.forename: T J
authors.initials: TJ
authors.lastname: Brown
authors.forename: S E
authors.initials: SE
authors.lastname: Webber
authors.forename: M L
authors.initials: ML
authors.lastname: Foster
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001851:Bone Diseases, Metabolic / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D019819:Budesonide / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D003899:Desoximetasone / Q000031:analogs & derivatives; D003911:Dextrans / Q000633:toxicity; D005270:Femur Head / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006132:Growth Plate / Q000187:drug effects; D006889:Hydroxycorticosteroids; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007442:Intubation, Intratracheal; D008297:Male; D015675:Osteocalcin / Q000037:antagonists & inhibitors / Q000097:blood; D011239:Prednisolone / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D011654:Pulmonary Edema / Q000139:chemically induced / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D003911:Dextrans; D005938:Glucocorticoids; D006889:Hydroxycorticosteroids; D007166:Immunosuppressive Agents; C000589029:RU24858; D015675:Osteocalcin; D003899:Desoximetasone; D019819:Budesonide; C025614:sephadex; D011239:Prednisolone