1. High-Dose Acetaminophen as a Treatment for Cancer.
- Author
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Wu, Jeffrey, Maller, Bradley, Kaul, Rujul, Galabow, Andrea, Bryan, Allyn, and Neuwelt, Alexander
- Subjects
DRUG toxicity ,HETEROCYCLIC compounds ,GLUTATHIONE ,HEPATOTOXICOLOGY ,ANTINEOPLASTIC agents ,ACETYLCYSTEINE ,JANUS kinases ,MOLECULAR structure ,TUMORS ,STAT proteins ,ACETAMINOPHEN ,PHARMACODYNAMICS - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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