PREVENTION OF CYTOKINE-INDUCED HYPOTENSION IN CANCER-PATIENTS BY THE PINEAL HORMONE MELATONIN

Hypotension is a frequent side-effect of cancer biotherapies with cyto kines. Cytokine-induced hypotension would mainly depend on the stimula tion of nitric oxide (NO) production, which represents the most effect ive endogenous vasodilator. Moreover, it has been proven that both bio logical activity and toxicity of cytokines are influenced by the psych oneuroendocrine system, in particular by the pineal hormone melatonin. To investigate the possible modulatory effect of melatonin on cytokin e cardiovascular toxicity, we evaluated the influence of a concomitant melatonin administration on interleukin-2(IL-2)- and tumour-necrosis- factor-alpha(TNF)-induced hypotension in advanced cancer patients. The study included 116 patients with advanced solid tumour, for whom no e ffective standard anticancer therapy was available, who underwent canc er biotherapy with IL-2 (3 x 10(6) IU/day s.c. every day, 6 days/week for 4 weeks) or with TNF (0.75 mglday i.v. for 5 days) as compassionat e treatment for their disease. Patients were randomized to be treated with or without a concomitant melatonin administration (40 mg/day oral ly in the evening, starting 7 days prior to cytokine injection). The o ccurrence of hypotension was significantly less frequent in patients c oncomitantly treated by melatonin than in those who re ceived the cyto kine alone, during either IL-2 or TNF immunotherapy (IL-2: 11/45 versu s 2/46, P<0.05; TNF: 10/23 versus 1/12, P<0.01). This study shows that melatonin may prevent hypotension occurring during cancer immunothera py with IL-2 or TNF. Since the pineal hormone has appeared to inhibit the activity of NO synthase from the endothelial cells, we suggest tha t melatonin may prevent cytokine-induced hypotension by inhibiting NO production, which plays an essential role in inducing hypotension duri ng IL-2 and TNF biotherapies.