达那唑治疗端粒疾病
Danazol Treatment for Telomere Diseases.
作者信息
Townsley Danielle M, Dumitriu Bogdan, Liu Delong, Biancotto Angélique, Weinstein Barbara, Chen Christina, Hardy Nathan, Mihalek Andrew D, Lingala Shilpa, Kim Yun Ju, Yao Jianhua, Jones Elizabeth, Gochuico Bernadette R, Heller Theo, Wu Colin O, Calado Rodrigo T, Scheinberg Phillip, Young Neal S
机构信息
From the Hematology Branch (D.M.T., B.D., D.L., B.W., C.C., N.H., N.S.Y.), the Cardiopulmonary Branch (A.D.M.), and the Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, the Center for Human Immunology, Autoimmunity, and Inflammation (A.B.), the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (S.L., Y.J.K., T.H.), Radiology and Imaging Sciences, Clinical Center (J.Y., E.J.), and the Medical Genetics Branch, National Human Genome Research Institute (B.R.G.), National Institutes of Health, Bethesda, MD; and the Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto (R.T.C.), and Clinical Hematology, Antônio Ermírio de Moraes Cancer Center, Hospital São José and Beneficência Portuguesa (P.S.), São Paulo.
出版信息
N Engl J Med. 2016 May 19;374(20):1922-31. doi: 10.1056/NEJMoa1515319.
BACKGROUND
Genetic defects in telomere maintenance and repair cause bone marrow failure, liver cirrhosis, and pulmonary fibrosis, and they increase susceptibility to cancer. Historically, androgens have been useful as treatment for marrow failure syndromes. In tissue culture and animal models, sex hormones regulate expression of the telomerase gene.
METHODS
In a phase 1-2 prospective study involving patients with telomere diseases, we administered the synthetic sex hormone danazol orally at a dose of 800 mg per day for a total of 24 months. The goal of treatment was the attenuation of accelerated telomere attrition, and the primary efficacy end point was a 20% reduction in the annual rate of telomere attrition measured at 24 months. The occurrence of toxic effects of treatment was the primary safety end point. Hematologic response to treatment at various time points was the secondary efficacy end point.
RESULTS
After 27 patients were enrolled, the study was halted early, because telomere attrition was reduced in all 12 patients who could be evaluated for the primary end point; in the intention-to-treat analysis, 12 of 27 patients (44%; 95% confidence interval [CI], 26 to 64) met the primary efficacy end point. Unexpectedly, almost all the patients (11 of 12, 92%) had a gain in telomere length at 24 months as compared with baseline (mean increase, 386 bp [95% CI, 178 to 593]); in exploratory analyses, similar increases were observed at 6 months (16 of 21 patients; mean increase, 175 bp [95% CI, 79 to 271]) and 12 months (16 of 18 patients; mean increase, 360 bp [95% CI, 209 to 512]). Hematologic responses occurred in 19 of 24 patients (79%) who could be evaluated at 3 months and in 10 of 12 patients (83%) who could be evaluated at 24 months. Known adverse effects of danazol--elevated liver-enzyme levels and muscle cramps--of grade 2 or less occurred in 41% and 33% of the patients, respectively.
CONCLUSIONS
In our study, treatment with danazol led to telomere elongation in patients with telomere diseases. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01441037.).
背景
端粒维持和修复方面的基因缺陷会导致骨髓衰竭、肝硬化和肺纤维化，并增加患癌易感性。从历史上看，雄激素一直被用于治疗骨髓衰竭综合征。在组织培养和动物模型中，性激素可调节端粒酶基因的表达。
方法
在一项针对端粒疾病患者的1-2期前瞻性研究中，我们口服给予合成性激素达那唑，剂量为每日800mg，共24个月。治疗目标是减轻加速的端粒损耗，主要疗效终点是在24个月时测得的端粒年损耗率降低20%。治疗毒性作用的发生是主要安全性终点。在各个时间点对治疗的血液学反应是次要疗效终点。
结果
在纳入27例患者后，研究提前终止，因为在所有12例可对主要终点进行评估的患者中端粒损耗均减少；在意向性分析中，27例患者中有12例（44%；95%置信区间[CI]，26%至64%）达到主要疗效终点。出乎意料的是，与基线相比，几乎所有患者（12例中的11例，92%）在24个月时端粒长度增加（平均增加386bp[95%CI，178至593]）；在探索性分析中，在6个月时（21例患者中的16例；平均增加175bp[95%CI，79至271]）和12个月时（18例患者中的16例；平均增加360bp[95%CI，209至512]）观察到类似的增加。在3个月时可评估的24例患者中有19例（79%）以及在24个月时可评估的12例患者中有10例（83%）出现血液学反应。达那唑已知的不良反应——肝酶水平升高和肌肉痉挛——2级或以下分别发生在41%和33%的患者中。
结论
在我们的研究中，达那唑治疗导致端粒疾病患者的端粒延长。（由美国国立卫生研究院资助；ClinicalTrials.gov编号，NCT01441037。）
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