多柔比星联合或不联合美司钠给药后血浆肿瘤坏死因子-α及可溶性肿瘤坏死因子受体水平——一项随机交叉临床研究
Plasma TNF-α and Soluble TNF Receptor Levels after Doxorubicin with or without Co-Administration of Mesna-A Randomized, Cross-Over Clinical Study.
作者信息
Hayslip John, Dressler Emily V, Weiss Heidi, Taylor Tammy J, Chambers Mara, Noel Teresa, Miriyala Sumitra, Keeney Jeriel T R, Ren Xiaojia, Sultana Rukhsana, Vore Mary, Butterfield D Allan, St Clair Daret, Moscow Jeffrey A
机构信息
University of Kentucky, Markey Cancer Center, Lexington, Kentucky, United States of America; University of Kentucky, Division of Hematology and Blood and Marrow Transplantation, Lexington, Kentucky, United States of America.
University of Kentucky, Markey Cancer Center, Lexington, Kentucky, United States of America.
出版信息
PLoS One. 2015 Apr 24;10(4):e0124988. doi: 10.1371/journal.pone.0124988. eCollection 2015.
PURPOSE
Chemotherapy-induced cognitive impairment (CICI) is a common sequelae of cancer therapy. Recent preclinical observations have suggested that CICI can be mediated by chemotherapy-induced plasma protein oxidation, which triggers TNF-α mediated CNS damage. This study evaluated sodium-2-mercaptoethane sulfonate (Mesna) co-administration with doxorubicin to reduce doxorubicin-induced plasma protein oxidation and resultant cascade of TNF-α, soluble TNF receptor levels and related cytokines.
METHODS
Thirty-two evaluable patients were randomized using a crossover design to receive mesna or saline in either the first or second cycle of doxorubicin in the context of a standard chemotherapy regimen for either non-Hodgkin lymphoma or breast cancer. Mesna (360 mg/m2) or saline administration occurred 15 minutes prior and three hours post doxorubicin. Pre-treatment and post-treatment measurements of oxidative stress, TNF-α and related cytokines were evaluated during the two experimental cycles of chemotherapy.
RESULTS
Co-administration of mesna with chemotherapy reduced post-treatment levels of TNF-related cytokines and TNF-receptor 1 (TNFR1) and TNF-receptor 2 (TNFR2) (p = 0.05 and p = 0.002, respectively). Patients with the highest pre-treatment levels of each cytokine and its receptors were the most likely to benefit from mesna co-administration.
CONCLUSIONS
The extracellular anti-oxidant mesna, when co-administered during a single cycle of doxorubicin, reduced levels of TNF-α and its receptors after that cycle of therapy, demonstrating for the first time a clinical interaction between mesna and doxorubicin, drugs often coincidentally co-administered in multi-agent regimens. These findings support further investigation to determine whether rationally-timed mesna co-administration with redox active chemotherapy may prevent or reduce the cascade of events that lead to CICI.
TRIAL REGISTRATION
clinicaltrials.gov NCT01205503.
目的
化疗诱导的认知障碍（CICI）是癌症治疗常见的后遗症。最近的临床前观察表明，CICI可由化疗诱导的血浆蛋白氧化介导，这会引发肿瘤坏死因子-α（TNF-α）介导的中枢神经系统损伤。本研究评估了2-巯基乙烷磺酸钠（美司钠）与多柔比星联合使用，以减少多柔比星诱导的血浆蛋白氧化以及由此引发的TNF-α、可溶性TNF受体水平及相关细胞因子的级联反应。
方法
32例可评估患者采用交叉设计随机分组，在非霍奇金淋巴瘤或乳腺癌的标准化疗方案中，于多柔比星治疗的第一个或第二个周期接受美司钠或生理盐水。美司钠（360mg/m²）或生理盐水在多柔比星给药前15分钟及给药后3小时给予。在两个化疗实验周期中评估氧化应激、TNF-α及相关细胞因子的治疗前和治疗后测量值。
结果
美司钠与化疗联合使用可降低治疗后TNF相关细胞因子以及TNF受体1（TNFR1）和TNF受体2（TNFR2）的水平（分别为p = 0.05和p = 0.002）。每种细胞因子及其受体治疗前水平最高的患者最有可能从美司钠联合使用中获益。
结论
细胞外抗氧化剂美司钠在多柔比星单周期治疗期间联合使用时，可降低该周期治疗后TNF-α及其受体的水平，首次证明了美司钠与多柔比星之间的临床相互作用，这两种药物在多药方案中常同时使用。这些发现支持进一步研究，以确定美司钠与氧化还原活性化疗药物合理的联合给药时间是否可预防或减少导致CICI的一系列事件。
试验注册
clinicaltrials.gov NCT01205503
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