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INTRODUCTION

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The interferons (IFNs) are a family of proteins that are grouped into three classes α, β, and γ. They were discovered based on their ability to "interfere" with viral infection of cells. Subsequent study has revealed a panoply of biological actions including immunomodulatory, antiproliferative, and antiangiogenic effects (1). Nearly all the oncologic applications of the IFNs have been of the α class.

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The α and β IFNs are encoded by a series of genes on chromosome 9p. At least 12 varieties of α IFN exist. A product composed of several species of α IFN produced by stimulated lymphoblasts exists (Wellferon, Burroughs Wellcome), but the predominant forms of IFN in clinical use are recombinant molecules of a single species of α, specifically α2. IFN-α2 is 165 amino acids in length with a molecular weight of about 23 kD. IFN-α2a (Hoffmann-La Roche) differs from IFN-α2b (Schering-Plough) by a single amino acid; IFN-α2a has a lysine at position 23, and IFN-α2b has an arginine. IFN-β has no established role in cancer treatment but is widely used to suppress relapses in multiple sclerosis.

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IFN-γ maps to chromosome 12, is 143 amino acids in length, and has minimal sequence homology with IFNs α and β. Its cellular receptor is distinct from the receptor for IFNs α and β, but both types of receptors are widely expressed on all nucleated cells and tissues. Each cell expresses 100–2000 receptors, and the binding constants (Kd) are between 10–11 and 10–9 M. The α receptor has two chains, one of which is associated with Tyk2 tyrosine kinase and one with JAK1 kinase (2). The genes for the α receptor map to chromosome 21q22.1. The γ receptor also has two chains, one of which is associated with JAK1 kinase and one with JAK2 kinase. The γ receptor genes are on chromosome 6q. Figure 13-1 shows the two forms of receptor for the three classes of IFNs.

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FIGURE 13-1

Components of the interferon (IFN) signaling pathways. The major components responsible for relaying IFN-mediated signals from the cell surface to the regulatory elements of IFN-stimulated genes are represented. GAS, IFN-γ activated site; IFNAR, IFN-α receptor; IFNGR, IFN-γ receptor; ISRE, IFN-stimulated response element; JAK, Janus kinase; SHP, src-homology 2 domain-containing protein tyrosine phosphatase; SOCS, suppressor of cytokine signaling; STAT, signal transducer and activator of transcription; Tyk, JAK family kinase. Small black bars represent tyrosine residues that become phosphorylated and induce complex formation.

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IFNs have been approved for use in seven types of cancer, several viral diseases, an autoimmune disease (multiple sclerosis; IFN-β), and an immune deficiency disease (chronic granulomatous disease; IFN-γ) (Table 13-1). In addition to the tumors listed in Table 13-1, IFN-α also has antitumor activity in cutaneous T-cell lymphoma. However, for most of these cancers, IFN ...

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