Overexpression of Glucocorticoid Receptor ß Enhances Myogenesis and Reduces Catabolic Gene Expression.

Unlike the glucocorticoid receptor α (GRα), GR ß (GRß) has a truncated ligand-binding domain that prevents glucocorticoid binding, implicating GRα as the mediator of glucocorticoid-induced skeletal muscle loss. Because GRß causes glucocorticoid resistance, targeting GRß may be beneficial in impairing muscle loss as a result of GRα activity. The purpose of this study was to determine how the overexpression of GRß affects myotube formation and dexamethasone (Dex) responsiveness. We measured GR isoform expression in C2C12 muscle cells in response to Dex and insulin, and through four days of myotube formation. Next, lentiviral-mediated overexpression of GRß in C2C12 was performed, and these cells were characterized for cell fusion and myotube formation, as well as sensitivity to Dex via the expression of ubiquitin ligases. GRß overexpression increased mRNA levels of muscle regulatory factors and enhanced proliferation in myoblasts. GRß overexpressing myotubes had an increased fusion index. Myotubes overexpressing GRß had lower forkhead box O3 (Foxo3a) mRNA levels and a blunted muscle atrophy F-box/Atrogen-1 (MAFbx) and muscle ring finger 1 (MuRF1) response to Dex. We showed that GRß may serve as a pharmacological target for skeletal muscle growth and protection from glucocorticoid-induced catabolic signaling. Increasing GRß levels in skeletal muscle may cause a state of glucocorticoid resistance, stabilizing muscle mass during exposure to high doses of glucocorticoids.

Induction paclitaxel, carboplatin, and infusional 5-FU followed by concurrent radiation therapy and weekly paclitaxel/carboplatin in the treatment of locally advanced head and neck cancer: a phase II trial of the Minnie Pearl Cancer Research Network.

PURPOSE: The purpose of this study was to evaluate the feasibility, toxicity, and efficacy of a novel combined-modality treatment for patients with locally advanced squamous carcinoma of the head and neck. PATIENTS AND METHODS: In this multicenter, community-based phase 11 study, 123 previously untreated patients with locally advanced squamous carcinoma of the head and neck received 6 weeks of induction chemotherapy followed by concurrent high-dose radiation therapy and weekly chemotherapy. Induction chemotherapy included paclitaxel (200 mg/m2, 1-hour i.v. infusion) on days 1 and 22, carboplatin (AUC 6.0 i.v.) on days 1 and 22, and 5-fluorouracil (225 mg/m2 per day, 24-hour continuous i.v. infusion) on days 1-43. After 1 week without therapy, radiation therapy, 1.8 Gy/day, 5 days weekly, to a total dose of 68.4 Gy, was administered to the primary site and the bilateral cervical lymph nodes. During radiation therapy, patients also received six weekly doses of paclitaxel (50 mg/m2, 1-hour i.v. infusion) and carboplatin (AUC 1.0 i.v). After completion of therapy, patients were restaged with computed tomographic and endoscopic examination; patients in complete remission were followed up without further treatment. RESULTS: One hundred twenty-three patients (74% with stage IV disease) entered this trial, and 111 patients (90%) completed the entire treatment course. Seventy of 116 evaluable patients (60%; 95% Cl, 51%-69%)had a clinical complete response to treatment. After a median follow-up of 24 months, the 2-and 3-year actuarial survivals were 66% and 51%, respectively. Local toxicity was moderately severe during combined-modality therapy; however, xerostomia has been the only frequent chronic toxicity of this program. CONCLUSIONS: This novel combined-modality treatment program, containing paclitaxel and avoiding the use of cisplatin, is feasible, is highly active, and can be administered with acceptable toxicity in a community-based setting. Aggressive nutritional support should be considered in patients receiving this regimen, to improve acute palliation and to maximize the delivery of combined-modality therapy. Further evaluation of this treatment program is warranted. Incorporation of various novel biologic agents, particularly the epidermal growth factor receptor antagonists, may further improve efficacy.