New pharmacokinetic and pharmacodynamic tools for interferon-alpha (IFN-alpha) treatment of human cancer.

Interferon alpha (IFN-alpha) has been widely used in the treatment of human solid and haematologic malignancies. Although the antitumour activity of IFN-alpha is well recognised at present, no major advances have been achieved in the last few years. Recent findings have provided new information on the molecular mechanisms of the antitumour activity of the cytokine. In fact, IFN-alpha appears to block cell proliferation, at least in part, through the induction of apoptotic effects. This cytokine can also regulate the progression of tumour cells through the different phases of the cell cycle inducing an increase of the expression of the cyclin-dependent kinase inhibitors p21 and p27. However, it must be considered that IFN-alpha is a physiologic molecule with ubiquitously expressed receptors that is likely to activate survival mechanisms in the cell. We have recently identified an epidermal growth factor (EGF) Ras-dependent protective response to the apoptosis induced by IFN-alpha in epidermoid cancer cells. The identification of tissue- and/or tumour-specific survival pathways and their selective targeting might provide a new approach to improve the efficacy of IFN-alpha-based treatment of human cancer. Moreover, new pegylated species of IFN-alpha are now available with a more favourable pharmacokinetic profile. We will review these achievements, and we will specifically address the topic of IFN-alpha-based molecularly targeted combinatory antitumour approaches.