Histamine has been demonstrated to be involved in cell proliferation, embryonic development, and tumour growth. These various biological effects are mediated through the activation of specific histamine receptors (H1, H2, H3, and H4) that differ in their tissue expression patterns and functions. Although many in vitro and in vivo studies of the modulatory roles of histamine in tumour development and metastasis have been reported, the effect of histamine in the progression of some types of tumours remains controversial; however, recent findings on the role of histamine in the immune system have shed new light on this question. This review focuses on the recent advances in understanding the roles of histamine and its receptors in tumour biology. We report our recent observations of the anti-tumoural effect of H1 histamine antagonists on experimental and human melanomas. We have found that in spite of exogenous histamine stimulated human melanoma cell proliferation, clonogenic ability and migration activity in a dose-dependent manner, the melanoma tumour growth was not modulated by in vivo histamine treatment. On the contrary, terfenadine-treatment in vitro induced melanoma cell death by apoptosis and in vivo terfenadine treatment significantly inhibited tumour growth in murine models. These observations increase our understanding of cancer biology and may inspire novel anticancer therapeutic strategies.

Multiferon® (HuIFN-alpha-Le) (MF) is a natural interferon alpha used in several countries for the treatment of selected viral infections and as an adjuvant treatment in different types of cancer, including melanoma. We have examined the influence of MF in vitro and in vivo in murine melanoma cells. B16F10 cells were treated with MF at different concentrations ranging from 0 to 1000 IU/mL and this substance had no effect on cell proliferation, migration or clonogenic abilities of the tumoral cells. However, in vivo studies with murine models after subcutaneous implantation of B16F10 cells showed that tumor volumes measured during the experiment and at sacrifice were significantly smaller in mice receiving MF (90 IU/mice 3 times a week) than in the control group (p<0.005). MF was well tolerated and no body weight loss or other sign of toxicity was observed in all groups. These results indicate that MF is active in vivo in murine experimental melanoma model without showing any direct antimelanoma activity in in vitro assays when used at doses mimicking the serum levels found in clinical practice in humans. We believe that the activation of the immune system following the administration of MF may be one of the mechanisms that explain the anti-tumoral effect of this drug.