High-Dose Acetaminophen as a Treatment for Cancer

被引:0
作者
Wu, Jeffrey [1 ]
Maller, Bradley [2 ,3 ]
Kaul, Rujul [2 ]
Galabow, Andrea [2 ]
Bryan, Allyn [2 ]
Neuwelt, Alexander [2 ]
机构
[1] Oregon Hlth & Sci Univ, Sch Med, Dept Neurol, 3181 Sam Jackson Pk Rd, Portland, OR 97239 USA
[2] Dept Vet Affairs, 1201 Broad Rock Blvd, Richmond, VA 23249 USA
[3] Virginia Commonwealth Univ, Sch Med, Dept Internal Med, 1201 E Marshall St, Richmond, VA 23298 USA
来源
LIVERS | 2024年 / 4卷 / 01期
关键词
acetaminophen; N-acetylcysteine; fomepizole; cancer; N-ACETYLCYSTEINE; CISPLATIN; HEPATOTOXICITY; EFFICACY; HEPATOBLASTOMA; CHEMOTHERAPY; TOXICITY; RESCUE; AMIDE;
D O I
10.3390/livers4010007
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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.
引用
收藏
页码:84 / 93
页数:10
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