Inhibition of the cyclooxygenase/lipoxygenase pathways to improve interferon alfa efficacy in chronic hepatitis C: A wrong track

Abstract

Because of its antiviral and immunomodulatory properties, interferon alfa (IFN-␣) has been widely used in the treatment of chronic hepatitis C, with rather disappointing results in terms of sustained viral clearance ratios when administered in monotherapy. 1 Among numerous effects, the fixation of IFN to its specific cellular receptor activates phospholipase A 2 , which catalyzes hydrolysis of phosphatidylcholine, releasing arachidonic acid. Arachidonic acid is then metabolized by cyclooxygenase into prostaglandins, by lipoxygenase into leukotrienes, and by epoxygenase into monooxygenated eicosanoids. It was shown in vitro that: (1) the latter act as second-messengers of IFN, resulting in interferon-stimulated response element (ISRE)-dependent transcription 2 ; (2) inhibition of cyclooxygenase or lipoxygenase enzymes results in amplification of IFN-␣-induced ISRE binding and gene expression. 2 Therefore, drugs inhibiting the cyclooxygenase pathway, such as nonstreroidal anti-inflammatory drugs (NSAIDs), might theoretically enhance the antiviral action of IFN by diverting arachidonic acid towards the epoxygenase pathway. In a large series of naive patients with chronic hepatitis C reported last year in HEPATOLOGY, Zarski et al. 3 found that neither the activity of the IFN-induced enzyme 2Ј-5Ј oligoadenylate synthetase, nor the ratio of sustained virological response to 6 months of therapy were increased by the adjunction of tenoxicam (an NSAID inhibiting the cyclooxygenase pathway) to IFN-␣. However, it must be stressed that, to date, attempts have been made to block the cyclooxygenase pathway only, so that arachidonic acid could have been diverted principally towards the lipooxygenase pathway, with only a marginal effect on ISRE-related transcription.We conducted a pilot study in patients with chronic hepatitis C having not responded to a previous course of IFN-␣ to evaluate the effect of a combination of IFN-␣ with tenoxicam and/or mesalazine, a drug with multiple actions including inhibition of lipoxygenase pathway 4 that is currently used in the treatment of inflammatory bowel disease. Eight patients (8 men, mean age 41.5 years, range 32-58), previously treated with 3 megaunits of IFN-␣2a (Roferon; Roche Products, Basel, Switzerland) 3 times per week for 6 months who did not respond were included after giving written informed consent. Five patients (group A) were randomly assigned to receive a combination of IFN-␣2a, 3 megaunits 3 times per week, plus tenoxicam, 20 mg/d orally, whereas 3 patients (group B) received a combination of IFN-␣2a at the same dose plus mesalazine, 4 g/d orally. This treatment was given for 3 months. During the next 3 months, all of the 8 patients received a triple combination of IFN-␣2a plus tenoxicam plus mesalazine at the same doses. The patients were followed-up for 6 months after treatment withdrawal. Alanine aminotransferase (ALT) activity and serum hepatitis C virus (HCV) RNA (Amplicor HCV; Roche Molecular Diagnostics, Pleasanton, CA) were measured before treatment, at month ...

Cyclooxygenase-2 inhibitor and interferon-β synergistically induce apoptosis in human hepatoma cells in vitro and in vivo

“…Several studies have suggested that combined administration of IFN-• with NSAIDs can improve virological response in chronic hepatitis C (39,40), although the opposite result has also been reported (41). Some of the proposed mechanisms for this synergism include increased STAT1 phosphorylation (42), and upregulation of serum 2'5'-oligoadenylate synthetase (43).…”