一项使用 S-谷胱甘肽化作为生物标志物的针对涉及肝脏的晚期实体瘤患者的双硫仑和葡萄糖酸铜的 1 期剂量递增研究。
A Phase 1 dose-escalation study of disulfiram and copper gluconate in patients with advanced solid tumors involving the liver using S-glutathionylation as a biomarker.
机构信息
Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA.
Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
出版信息
BMC Cancer. 2021 May 7;21(1):510. doi: 10.1186/s12885-021-08242-4.
BACKGROUND
Disulfiram and metals inactivate key oncoproteins resulting in anti-neoplastic activity. The goal of this study was to determine the maximum tolerated dose of copper when administered with disulfiram in patients with advanced solid tumors and liver involvement.
METHODS
Disulfiram 250 mg was administered daily in 28-day cycles. Four doses of copper gluconate were tested (2, 4, 6, and 8 mg of elemental copper) in a standard 3 + 3 dose escalation design. Patients were evaluated for dose limiting toxicities and response. Protein S-glutathionylation was evaluated as a pharmacodynamic marker.
RESULTS
Twenty-one patients were enrolled and 16 patients were evaluable for dose limiting toxicities. Among the 21 patients, there was a median of 4 lines of prior chemotherapy. Five Grade 3 toxicities were observed (anorexia, elevated aspartate aminotransferase or AST, elevated alkaline phosphatase, fever, and fatigue). Response data was available for 15 patients. Four patients had stable disease with the longest duration of disease control being 116 days. The median duration of treatment for evaluable patients was 55 days (range 28-124). Reasons for discontinuation included functional decline, disease progression, and disease-associated death. Increased S-glutathionylation of serum proteins was observed with treatment.
CONCLUSION
Disulfiram 250 mg daily with copper gluconate (8 mg of elemental copper) was well-tolerated in patients with solid tumors involving the liver and was not associated with dose limiting toxicities. While temporary disease stabilization was noted in some patients, no objective responses were observed. Treatment was associated with an increase in S-glutathionylation suggesting that this combination could exert a suppressive effect on cellular growth and protein function.
TRIAL REGISTRATION
NCT00742911 , first posted 28/08/2008.
背景
双硫仑和金属会使关键致癌蛋白失活，从而产生抗肿瘤活性。本研究的目的是确定在晚期实体瘤和肝受累患者中，与双硫仑联合使用时铜的最大耐受剂量。
方法
双硫仑 250mg 每天在 28 天周期中给药。在标准的 3+3 剂量递增设计中，测试了 4 种葡萄糖酸铜剂量（2、4、6 和 8mg 元素铜）。评估患者的剂量限制毒性和反应。蛋白质 S-谷胱甘肽化被评估为药效学标志物。
结果
共纳入 21 例患者，16 例患者可评估剂量限制毒性。在 21 例患者中，中位既往化疗线数为 4 线。观察到 5 例 3 级毒性（厌食、天门冬氨酸氨基转移酶或 AST 升高、碱性磷酸酶升高、发热和疲劳）。15 例患者可获得反应数据。4 例患者病情稳定，疾病控制最长时间为 116 天。可评估患者的中位治疗时间为 55 天（范围 28-124）。停药的原因包括功能下降、疾病进展和与疾病相关的死亡。治疗后观察到血清蛋白的 S-谷胱甘肽化增加。
结论
每日给予双硫仑 250mg 和葡萄糖酸铜（8mg 元素铜）在肝受累的实体瘤患者中耐受性良好，且无剂量限制毒性。虽然一些患者出现了暂时的疾病稳定，但未观察到客观缓解。治疗与 S-谷胱甘肽化增加相关，表明该联合用药可能对细胞生长和蛋白功能产生抑制作用。
试验注册
NCT00742911，首次发布于 2008 年 8 月 28 日。
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