Lin Jianqing, Zhan Tingting, Duffy Danielle, Hoffman-Censits Jean, Kilpatrick Deborah, Trabulsi Edouard J, Lallas Costas D, Chervoneva Inna, Limentani Kimberly, Kennedy Brooke, Kessler Sarah, Gomella Leonard, Antonarakis Emmanuel S, Carducci Michael A, Force Thomas, Kelly Wm Kevin
Department of Medical Oncology, Jefferson Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107.
Department of Pharmacology and Experimental Therapeutics (Biostatistics), Jefferson Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107.
Am J Cancer Ther Pharmacol. 2014 Sep 7;2(1):21-32.
Digoxin was found to inhibit prostate cancer (PCa) growth via the inhibition of HIF-1α synthesis in a mouse model. We hypothesized that a therapeutic dose of digoxin could inhibit human PCa growth and disease progression.
An open label, single arm pilot study was performed. Patients (pts) with non-metastatic, biochemically relapsed PCa with prostate specific antigen doubling time (PSADT) of 3-24 months and no hormonal therapy within the past 6 months were enrolled. All pts had testosterone > 50 ng/dL at baseline. Digoxin was taken daily with dose titration to achieve a target therapeutic level (0.8 - 2 ng/ml); patients had routine follow-up including cardiac monitoring with 12-lead electrocardiograms (ECGs) and digoxin levels. The primary endpoint was the proportion of pts at 6 months post-treatment with a PSADT ≥ 200% from the baseline. HIF-1α downstream molecule vascular endothelial growth factor (VEGF) was measured in plasma.
Sixteen pts were enrolled and 14 pts finished the planned 6 months of treatment. Twenty percent (3/15) of the pts had PSA decrease >25% from baseline with a medium duration of 14 months. At 6 months, 5 of 13 (38%) pts had PSADT ≥ 200% of the baseline PSADT and were continued on study for an additional 24 weeks of treatment. Two patients had durable PSA response for more than 1 year. Digoxin was well tolerated with possible relation of one grade 3 back pain. No patients had evidence of digoxin toxicity. The digoxin dose was lowered in 2 patients for significant ECGs changes (sinus bradycardia and QT prolongation), and there were probable digoxin-related ECG changes in 3 patients. Plasma VEGF was detected in 4 (25%) patients.
Digoxin was well tolerated and showed a prolongation of PSDAT in 38% of the patients. However, there was no significant difference comparing that of similar patients on placebo from historical data. Digoxin at the dose used in this study may have limited benefit for patients with biochemically relapsed prostate cancer.
在小鼠模型中发现地高辛可通过抑制缺氧诱导因子-1α（HIF-1α）合成来抑制前列腺癌（PCa）生长。我们推测治疗剂量的地高辛可抑制人PCa生长和疾病进展。
开展了一项开放标签、单臂试点研究。纳入前列腺特异性抗原倍增时间（PSADT）为3 - 24个月且在过去6个月内未接受激素治疗的非转移性、生化复发PCa患者。所有患者基线时睾酮水平>50 ng/dL。每日服用地高辛并进行剂量滴定以达到目标治疗水平（0.8 - 2 ng/ml）；患者接受常规随访，包括通过12导联心电图（ECG）进行心脏监测和检测地高辛水平。主要终点是治疗6个月时PSADT较基线增加≥200%的患者比例。检测血浆中HIF-1α下游分子血管内皮生长因子（VEGF）。
纳入16例患者，14例患者完成了计划的6个月治疗。20%（3/15）的患者前列腺特异性抗原（PSA）较基线下降>25%，中位持续时间为14个月。6个月时，13例患者中有5例（38%）PSADT≥基线PSADT的200%，并继续接受另外24周的治疗。2例患者PSA持续缓解超过1年。地高辛耐受性良好，可能与1例3级背痛有关。无患者出现地高辛毒性证据。2例患者因显著的心电图变化（窦性心动过缓和QT延长）降低了地高辛剂量，3例患者可能出现了与地高辛相关的心电图变化。4例（25%）患者检测到血浆VEGF。
地高辛耐受性良好，38%的患者PSDAT延长。然而，与历史数据中接受安慰剂治疗的类似患者相比，无显著差异。本研究中使用的剂量的地高辛对生化复发前列腺癌患者的益处可能有限。
