Comparison of Corticotropin-Releasing Factor Dexamethasone and Temozolomide: Treatment Efficacy and Toxicity in U87 and C6 Intracranial Gliomas

摘要

Treatment of cerebral tumors and peritumoral brain edema remains a clinical challenge and is associated with high morbidity and mortality. Dexamethasone (DEX) is an effective drug to treat brain edema, but is associated with well-described side effects. Corticorelin acetate (Xerecept) or human corticotrophin releasing factor (hCRF) is a comparatively new drug and was evaluated in two orthotopic glioma models (U87 and C6), by a direct comparison with dexamethasone and temozolomide.In vitro mono- and combination-treatments showed a variable response in 6 different glioma cell lines. In vivo studies showed a dose-dependent effect of hCRF (0.03 and 0.1 mg/kg/q12h) on survival of U87 intracranial xenograft-bearing animals [median survival: control 41 days (95% CI 25–61 d); “low-hCRF” 74.5 d (95% CI 41–88 d); “high-hCRF” >130 d (95% CI not reached)]. Dexamethasone treatment had no effect on survival, but significant toxicity was observed. A survival benefit was observed with TMZ and TMZ + hCRF - treated animals, but with significant TMZ toxicity. C6-bearing animals showed no survival benefit, but similar treatment toxicities. The difference in hCRF-treatment response between U87- and C6-intracranial gliomas can be explained by a difference in receptor expression. RT-PCR identified CRF2r mRNA in U87-xenografts; no CRF-receptors were identified in C6-xenografts.HCRF was more effective than either dexamethasone or temozolomide in the treatment of U87 xenografts, with long-term survivors and only mild toxicity. HCRF therapeutic efficacy appears to be dependent on tumor hCRF-receptor expression. These results support further clinical assessment hCRF therapeutic efficacy and levels of CRFr expression in different human gliomas.