促肾上腺皮质激素释放因子、地塞米松与替莫唑胺治疗颅内 U87 和 C6 胶质瘤的疗效和毒性比较
Comparison of corticotropin-releasing factor, dexamethasone, and temozolomide: treatment efficacy and toxicity in U87 and C6 intracranial gliomas.
机构信息
Department of Neurology and Radiology, Sloan Kettering Institute Molecular Pharmacology and Chemistry Program, Inc, New York, NY 10065, USA.
出版信息
Clin Cancer Res. 2011 May 15;17(10):3282-92. doi: 10.1158/1078-0432.CCR-10-3203. Epub 2011 Mar 8.
UNLABELLED
PURPOSE/EXPERIMENTAL DESIGN: Treatment of cerebral tumors and peritumoral brain edema remains a clinical challenge and is associated with high morbidity and mortality. Dexamethasone is an effective drug for treating brain edema, but it is associated with well-documented side effects. Corticorelin acetate (Xerecept) or human corticotrophin-releasing factor (hCRF) is a comparatively new drug and has been evaluated in two orthotopic glioma models (U87 and C6), by a direct comparison with dexamethasone and temozolomide.
RESULTS
In vitro combination therapy and monotherapy 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); "low-hCRF" 74.5 days (95% CI 41-88); "high-hCRF" >130 days (95% CI not reached)]. Dexamethasone treatment had no effect on survival, but significant toxicity was observed. A survival benefit was observed with temozolomide and temozolomide + hCRF-treated animals but with significant temozolomide toxicity. C6-bearing animals showed no survival benefit, but there were 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.
CONCLUSIONS
hCRF was more effective than either dexamethasone or temozolomide in the treatment of U87 xenografts, and results included improved prognosis with long-term survivors and only mild toxicity. The therapeutic efficacy of hCRF seems to be dependent on tumor hCRF receptor (CRFr) expression. These results support further clinical assessment of the therapeutic efficacy of hCRF and levels of CRFr expression in different human gliomas.
目的/实验设计：脑肿瘤和肿瘤周围脑水肿的治疗仍然是一个临床挑战，与之相关的发病率和死亡率很高。地塞米松是治疗脑水肿的有效药物，但它也有明确记载的副作用。醋酸促肾上腺皮质激素释放因子（Xerecept）或人促皮质素释放因子（hCRF）是一种相对较新的药物，已在两种原位胶质瘤模型（U87 和 C6）中进行了评估，与地塞米松和替莫唑胺进行了直接比较。
结果
在 6 种不同的神经胶质瘤细胞系中，体外联合治疗和单药治疗显示出不同的反应。体内研究显示，hCRF（0.03 和 0.1mg/kg，q12h）对 U87 颅内异种移植动物的生存有剂量依赖性影响[中位生存：对照组-41 天（95%CI25-61）；“低-hCRF”74.5 天（95%CI41-88）；“高-hCRF”>130 天（95%CI 未达到）]。地塞米松治疗对生存没有影响，但观察到明显的毒性。替莫唑胺和替莫唑胺+hCRF 治疗的动物有生存获益，但替莫唑胺毒性明显。C6 荷瘤动物没有生存获益，但治疗毒性相似。U87 和 C6 颅内神经胶质瘤中 hCRF 治疗反应的差异可以用受体表达的差异来解释。RT-PCR 在 U87 异种移植瘤中鉴定出 CRF2r mRNA；在 C6 异种移植瘤中未鉴定出 CRF 受体。
结论
hCRF 治疗 U87 异种移植瘤比地塞米松或替莫唑胺更有效，结果包括长期生存者预后改善和仅有轻度毒性。hCRF 的治疗效果似乎取决于肿瘤 hCRF 受体（CRFr）的表达。这些结果支持进一步评估 hCRF 的治疗效果以及不同人神经胶质瘤中 CRFr 表达水平的临床评估。
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