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-alpha(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 x 10(6) 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, P < 0.05; TNF: 10/23 versus 1/12, P < 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.

Today, it is known that all human biological functions are under two fundamental regulatory systems, consisting of the endocrine system and the cytokine network. Moreover, it has been shown that the cytokines released from the activated immune cells do not influence only immune functions, but also the whole biological system, including the various metabolic activities, the cardiovascular system, and the functionless of the neuroendocrine system itself. Unfortunately, despite the well-demonstrated importance of cytokines in maintaining the status of health, from a clinical point of view the routine evaluation of the cytokine system still remains unconsidered to establish the status of health, since it is investigated only in severe conditions, such as septic shock, disseminated intravascular coagulation and respiratory distress, which have been demonstrated to be due to an abnormal endogenous production of inflammatory cytokines, namely IL-6, TNF-alpha, and IL-1 beta. This clinical deficiency was depended on several factors, particularly on the complexity of cytokine interactions themselves, but also on the decision to use artificial molecules, such as monoclonal antibodies against the various cytokines, to counteract their eventual abnormally enhanced endogenous production, rather than to investigate the mechanisms responsible for their altered production and to correct eventual alterations. The main reason of the complexity of the cytokine network is related to the fact that the interactions occurring among the different cytokines are often founded on positive feedback mechanisms, then on reciprocal stimulatory actions, while the endocrine system is substantially based on negative feedback circuits. The aim of the present review is to propose a synthetic knowledge regarding the main effects and the source of origin of each single interleukin discovered up to now, to elaborate a first preliminary fundamental physiology of the cytokine network.

Recent observations showed that host may regulate either endocrinologically or immunologically tumor growth and differentiation, perhaps by modulating oncogene expression. Within the endocrine system, the pineal hormone, melatonin, seems to play an important antineoplastic role. To investigate its secretion in relation to tumor growth, we have evaluated the daily serum levels of melatonin in a group of 25 untreated breast cancer patients with a locally limited disease. Tumor cell proliferation was established by measuring Ki-67 labeling rate. As controls, 46 healthy women were considered. Breast cancer patients showed significantly higher mean values of melatonin than controls. Moreover, patients with negative Ki-67 labeling rate had significantly higher levels of the pineal hormone than those with a positive Ki-67 rate. Since tumors with high growth fraction present a worse prognosis, this study would suggest that the relief of an increased melatonin secretion represents a favorable prognostic sign, because of its association with less proliferating breast cancers.

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