Wu Jeffrey, Maller Bradley, Kaul Rujul, Galabow Andrea, Bryan Allyn, Neuwelt Alexander
Department of Neurology, School of Medicine, Oregon Health and Sciences University, 3181 Sam Jackson Park Rd., Portland, OR 97239, USA.
Department of Veterans Affairs, 1201 Broad Rock Blvd, Richmond, VA 23249, USA.
Livers. 2024 Jan 31;4(1):84-91. doi: 10.3390/livers4010007.
The use of high-dose acetaminophen (AAP) with n-acetylcysteine (NAC) rescue was studied as an anti-cancer treatment in phase I trials with promising signals of anti-tumor efficacy. Correlative analysis suggested that AAP has a free-radical-independent mechanism of anti-tumor activity-in contrast to the well-established mechanism of AAP hepatotoxicity. Subsequent "reverse translational" studies in the pre-clinical setting have identified novel mechanisms of action of high-dose AAP, including modulation of JAK-STAT signaling in both the tumor cell and the tumor immune microenvironment. Importantly, these effects are free-radical-independent and not reversed by concurrent administration of the established AAP rescue agents fomepizole and NAC. By administering high-dose AAP concurrently with fomepizole and NAC, 100-fold higher AAP levels than those of standard dosing can be achieved in mice without detected toxicity and with substantial anti-tumor efficacy against commonly used mouse models of lung and breast cancer that are resistant to standard first-line anti-cancer therapies. With these recent advances, additional clinical trials of high-dose AAP with concurrent NAC and fomepizole-based rescue are warranted.
在I期试验中，研究了使用大剂量对乙酰氨基酚（AAP）联合N-乙酰半胱氨酸（NAC）解救作为一种抗癌治疗方法，试验显示出有前景的抗肿瘤疗效信号。相关分析表明，AAP具有不依赖自由基的抗肿瘤活性机制，这与已明确的AAP肝毒性机制形成对比。随后在临床前环境中进行的“反向转化”研究确定了大剂量AAP的新作用机制，包括对肿瘤细胞和肿瘤免疫微环境中JAK-STAT信号通路的调节。重要的是，这些作用不依赖自由基，并且不会因同时给予已有的AAP解救药物甲吡唑和NAC而逆转。通过同时给予大剂量AAP与甲吡唑和NAC，在小鼠中可实现比标准给药高100倍的AAP水平，且未检测到毒性，同时对常用的对标准一线抗癌疗法耐药的肺癌和乳腺癌小鼠模型具有显著的抗肿瘤疗效。鉴于这些最新进展，有必要开展大剂量AAP联合NAC和基于甲吡唑的解救方案的更多临床试验。
