High-Dose Acetaminophen with Concurrent CYP2E1 Inhibition Has Profound Anticancer Activity without Liver Toxicity

Abstract

Acetaminophen (AAP) is metabolized by a variety of pathways such as sulfation, glucuronidation and fatty acid amide hydrolase-mediated conversion to the active analgesic metabolite AM404. CYP2E1-mediated metabolism to the hepatotoxic reactive metabolite NAPQI (N-acetyl-p-benzoquinone imine) is a minor metabolic pathway that has not been clearly linked to AAP therapeutic benefits yet definitely leads to AAP liver toxicity. N-acetylcysteine (NAC) (an antioxidant) and fomepizole (a CYP2E1 inhibitor) are clinically used for the treatment of AAP toxicity. Mice treated with AAP in combination with fomepizole (+/-NAC) were assessed for liver toxicity by histology and serum chemistry. Anti-cancer activity of AAP with NAC and fomepizole rescue was assessed in vitro and in vivo. Fomepizole with or without NAC completely prevented AAP-induced liver toxicity. In vivo, high dose AAP with NAC/fomepizole rescue had profound anti-tumor activity against commonly used 4T1 breast tumor and LLC lung tumor models and no liver toxicity was detected. The anti-tumor efficacy was reduced in immune-compromised NSG mice, suggesting an immune mediated mechanism of action. In conclusion, using fomepizole-based rescue, we were able to treat mice with 100-fold higher than standard dosing of AAP (650 mg/kg) without any detected liver toxicity and substantial antitumor activity.

High-Dose Acetaminophen as a Treatment for Cancer

“…Subsequently, however, Wolchok et al observed grade IV liver toxicity in two patients treated with 20 g/m 2 AAP [18]; the maximum tolerated dose was set at 15 g/m 2 AAP. In our pre-clinical mouse models, higher doses of AAP could be tolerated without hepatotoxicity when administered with fomepizole-based rescue strategies [32] relative to the NAC regimens used in the initial clinical trials. Human trials are needed to comprehensively evaluate the safety profile, pharmacokinetics, and pharmacodynamics of high-dose AAP with fomepizole-based rescue across a range of doses in patients with advanced cancer.…”

“…The active AAP metabolite AM404 is generated in a CYP2E1-independent manner (Figure 2) [31]. While fomepizole prevents AAP hepatotoxicity in vivo, fomepizole did not reverse the anti-tumor effects of AAP in vitro or in vivo [32]-likely because CYP2E1 is expressed selectively in the liver (Figure 1) [19]. In fact, using fomepizole-based rescue, we were able to safely dose-escalate AAP to the levels needed for profound anti-tumor activity, 100-fold higher than standard AAP dosing, in commonly used mouse cancer models (LLC lung cancer and 4T1 breast cancer) without any detected toxicity [32].…”