PO.CL11.02 · 临床研究
N-乙酰半胱氨酸在癌症相关认知障碍的转化性卵巢癌模型中的药代动力学与神经保护作用
N-acetylcysteine pharmacokinetics and neuroprotection in a translational ovarian cancer model of cancer-related cognitive impairment
该海报暂无可下载的资料
AACR 官方页面
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：铂类化疗是卵巢癌治疗标准方案的一部分，然而超过70%的患者在治疗期间和治疗后会出现癌症相关认知障碍（CRCI）。顺铂诱导的CRCI与血浆细胞因子改变、线粒体功能障碍和谷胱甘肽耗竭相关。在卵巢癌异种移植大鼠模型中，抗氧化剂N-乙酰半胱氨酸（NAC；250 mg/kg，腹腔注射）可预防顺铂诱导的CRCI。为给一项针对卵巢癌患者CRCI预防的口服NAC的1期研究提供依据，我们比较了口服和腹腔注射NAC给药对有或无卵巢癌的雌性大鼠的脑和血液谷胱甘肽、血浆细胞因子、循环NAC水平及认知的影响。
方法：荷SKOV3.ip1异种移植瘤的雌性RNU大鼠接受顺铂（5 mg/kg，腹腔注射），每两周一次，共四个周期，同时给予或不给予NAC（250 mg/kg/天，腹腔注射），在每个周期内、顺铂给药后10小时给药，持续五天。认知测试（新物体识别，NOR）在治疗完成后6-7周进行。对于NAC药代动力学研究，将70只非荷瘤雌性Sprague Dawley大鼠随机分配至溶媒、250 mg/kg NAC腹腔注射，以及159、212、265、370、476 mg/kg口服NAC，同时给予或不给予顺铂。在一个周期后2小时收集血浆、全血和脑组织，血浆NAC水平通过质谱法定量。
结果：接受或不接受顺铂治疗的荷卵巢瘤大鼠（OvT+VEH、OvT+CDDP）与非荷瘤对照（NT+VEH）相比，NOR辨别比降低（≤0.5，P=0.0207）。NAC预防了顺铂诱导的NOR任务障碍（OvT+CDDP vs. OvT+CDDP+NAC，P=0.0343）。顺铂在48小时内显著降低海马和额叶皮质谷胱甘肽水平，而250 mg/kg NAC腹腔注射给药可预防这一现象。NAC未改变顺铂的抗癌活性或生存。口服与腹腔注射给药后血浆NAC水平的比较分析正在进行中。
结论：NAC在一个具有临床相关性的卵巢癌啮齿动物模型中预防顺铂诱导的CRCI。正在进行的药代动力学分析将指导针对卵巢癌患者的口服NAC 1期研究的设计。
查看英文原文 English abstract
Background: Platinum-based chemotherapy is part of the standard of care for ovarian cancer treatment, yet more than 70% of patients develop cancer-related cognitive impairment (CRCI) during and after treatment. Cisplatin-induced CRCI is associated with alterations in plasma cytokines, mitochondrial dysfunction, and glutathione depletion. In an ovarian cancer xenograft rat model, the antioxidant N-acetylcysteine (NAC; 250 mg/kg, i.p.) prevented cisplatin-induced CRCI. To inform a Phase 1 study of oral NAC for CRCI prevention in ovarian cancer patients, we compared oral and i.p. NAC administration on brain and blood glutathione, plasma cytokines, circulating NAC levels, and cognition in female rats with or without ovarian cancer.
Methods: Female RNU rats bearing SKOV3.ip1 xenografts received cisplatin (5 mg/kg, i.p.) biweekly for four cycles with or without NAC (250 mg/kg/day, i.p.) administered for five days during each cycle, 10 hours after cisplatin. Cognitive testing (novel object recognition, NOR) was performed 6-7 weeks after treatment completion. For NAC pharmacokinetic studies, 70 female non-tumor-bearing Sprague Dawley rats were randomized to vehicle, 250 mg/kg NAC i.p., and 159, 212, 265, 370, 476 mg/kg oral NAC, with or without cisplatin. Plasma, whole blood, and brain tissue were collected 2 hours after one cycle, and plasma NAC levels were quantified by mass spectrometry.
Results: Ovarian tumor-bearing rats treated with or without cisplatin (OvT+VEH, OvT+CDDP) showed reduced NOR discrimination ratios (≤0.5) compared with non-tumor-bearing controls (NT+VEH, P=0.0207). NAC prevented cisplatin-induced impairments in the NOR task (OvT+CDDP vs. OvT+CDDP+NAC, P=0.0343). Cisplatin significantly reduced hippocampal and frontal cortex glutathione levels within 48 h, which was prevented by 250 mg/kg NAC, i.p. administration. NAC did not alter cisplatin's anti-cancer activity or survival. Comparative analysis of plasma NAC levels after oral vs. i.p. administration is ongoing.
Conclusions: NAC prevents cisplatin-induced CRCI in a clinically relevant ovarian cancer rodent model. Ongoing pharmacokinetic analyses will guide the design of a Phase 1 study of oral NAC in patients with ovarian cancer.
利益披露 Disclosure
N. Lomeli, None..
D. C. Pearre, None..
J. J. Lepe, None..
T. H. Taylor, None..
D. A. Bota, None.