Perspectives in Biomolecular Therapeutic Intervention in Cancer: From the Early to the New Strategies With Type I Interferons

Abstract

Interferon (IFN) was the first cytokine produced by recombinant DNA technology used in wide-spread clinical treatment of infectious diseases as well as malignancies. The IFN clinical potential was clearly realized from the outset. However, IFN represents one of the most controversial drugs of our time, as remarkable cycles of promise and disappointment have affected its development and use. Considerable evidence regarding anti-tumor activities of IFNs has been reported. In this paper we focus on molecular bases of the IFN system that may relate to its antitumor activities. Many of the numerous genes transcriptionally activated by IFNs have been shown to encode proteins that activate immune recognition of tumor cells, directly or indirectly exert tumor suppressor activity and/or control tumor cell cycle and programmed cell death. In addition, a physiological relevant function for endogenous type I IFN in cancer immunoediting process and a new way to IFN clinical use based on gene therapy or vaccine-like approaches have recently been suggested. The identification of selected tissue-specific and/or tumor-specific target pathways as well as of different type I IFN tumor escape and resistance mechanisms may provide novel approaches in the search for new IFN-based therapeutic strategies to circumvent cancer disease or improve clinical outcome. Promising IFN treatment has been recently defined by using novel pharmaceutical preparations with a more favourable pharmacokinetic response, also in combination with other bioreagents or other modalities of therapy. Translational research, linking both basic and clinical research, will lead to a new rationale for the use of IFN in cancer therapy.

Gene expression profiles predicting the response to IFN-β and a combination of temozolomide and IFN-β in malignant gliomas

“…The human type I IFN family includes 13 IFN-α genes, one IFN-β gene and two IFN-ω genes (27). It is now accepted that most nucleated cells are capable of producing type I IFN, whereas type II IFN production is restricted to immune system cells (5). All members of the type I IFN family transmit signals through a receptor complex composed of two subunits, IFNAR-1 and IFNAR-2.…”

“…It is conceivable that numerous direct effects may play a central role in the overall antitumor response, such as downregulation of oncogene expression, induction of differentiation, tumor suppressor genes and programmed cell death, and inhibition of cell cycle progression (5). Furthermore, IFN-β has consistently been proven to be more potent than IF Ns-α in inducing antiproliferative effects and apoptosis (5,28).…”

IRF9 and STAT1 are required for IgG autoantibody production and B cell expression of TLR7 in mice

“…The anti-neoplastic properties of IFNs have been well documented, and STAT1 mediates the antiproliferative and proapoptotic effects of both IFN-Is and IFN-γ (53, 54). Recombinant IFN-α has been used successfully to treat a variety of malignancies (55). The higher rate of plasmacytoma induction in both Irf9 -/-and Stat1 -/-mice is therefore not surprising given their susceptible BALB/c genetic background, although the mechanism of this induction remains to be elucidated.…”

Viral defense, carcinogenesis and ISG15: Novel roles for an old ISG

“…The IFNs have shown clinical efficacy, as single agent therapy and in combination therapy, for the treatment of multiple hematologic and solid malignancies, as reviewed (63,64). Use of IFN in cancer therapy, however, has been limited by significant toxicity with dose escalation and by resistance to therapy.…”