Prevention of cytokine-induced hypotension in cancer patients by the pineal hormone melatonin

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Abstract
Hypotension is a frequent side-effect of cancer biotherapies with cytokines. Cytokine-induced hypotension would mainly depend on the stimulation of nitric oxide (NO) production, which represents the most effective endogenous vasodilator. Moreover, it has been proven that both biological activity and toxicity of cytokines are influenced by the psychoneuroendocrine system, in particular by the pineal hormone melatonin. To investigate the possible modulatory effect of melatonin on cytokine cardiovascular toxicity, we evaluated the influence of a concomitant melatonin administration on interleukin-2(IL-2)- and tumour-necrosis-factor-α(TNF)-induced hypotension in advanced cancer patients. The study included 116 patients with advanced solid tumour, for whom no effective standard anticancer therapy was available, who underwent cancer biotherapy with IL-2 (3 × 106 IU/day s.c. every day, 6 days/week for 4 weeks) or with TNF (0.75 mg/day i.v. for 5 days) as compassionate treatment for their disease. Patients were randomized to be treated with or without a concomitant melatonin administration (40 mg/day orally in the evening, starting 7 days prior to cytokine injection). The occurrence of hypotension was significantly less frequent in patients concomitantly treated by melatonin than in those who received the cytokine alone, during either IL-2 or TNF immunotherapy (IL-2: 11/45 versus 2/46,PP<0.01). This study shows that melatonin may prevent hypotension occurring during cancer immunotherapy with IL-2 or TNF. Since the pineal hormone has appeared to inhibit the activity of NO synthase from the endothelial cells, we suggest that melatonin may prevent cytokine-induced hypotension by inhibiting NO production, which plays an essential role in inducing hypotension during IL-2 and TNF biotherapies.