Cytokines are soluble proteins or glycoproteins that exert trophic effects on a variety of targets based on the expression of particular ligand-specific receptors on the target. All of the cytokines have not yet been identified; but at this time, more than 80 different molecules have been defined. The same cytokine can exert different effects on different cells and tissues. However, the biochemical consequences within the cell of ligand binding to its cellular receptor are similar among all the targets. A number of cytokines have been evaluated for their antitumor effects including the interferons, interleukin-1 (IL1), tumor necrosis factor, IL4, IL12, and others. The rationale for testing these agents as antitumor agents is twofold. First, many of these agents stimulate cells of the immune system, an effect that could promote the immunological killing of the tumor cells. Second, many neoplastic cells retain the cytokine receptors of their normal counterparts; thus, direct biological and potentially antitumor effects are theoretically possible.
Currently, only interferon-α (Chapter 13) and IL2 are approved for use as anticancer agents. Most other tested cytokines have either had little or no antitumor effect or were too toxic when administered systemically as a pharmacologic agent. In general, cytokines work physiologically as paracrine signals coordinating cellular responses in a localized area of release. It has been estimated that in the course of trying to develop IL2 as a therapeutic agent, we administered more of the agent to a few hundred patients than had been produced physiologically in the courses of their entire lives by every man and woman who ever lived.
Interleukin-2 (IL2) is a glycoprotein composed of 133 amino acids and has a molecular weight of 15 kD. It is structurally related to IL4, IL15, and granulocyte-macrophage colony-stimulating factor (GM-CSF). It is normally produced by stimulated T cells and NK cells and acts to promote the proliferation of activated T cells. Resting T cells do not express IL2 receptors and do not respond to the cytokine.
The IL2 receptor has three components: an α-chain, a 55-kD component, also known as CD25, that has only 13 amino acids located intracellularly and functions mainly in binding to IL2; a β-chain, a 75 kD component with a large intracellular component involved in signaling; and the common γ-chain, a 64-kD component called "common" because it is also a shared signaling component of receptors for IL4, IL7, IL9, IL15, and IL21. IL2 binds to the three-component high-affinity receptor with a Kd of 10 pmol/l; in the absence of the α-chain, IL2 binding is termed intermediate and is about 100-fold reduced. High-affinity receptors are mainly expressed on activated T cells; intermediate affinity receptors are expressed on monocytes and NK cells.
Biologic activity. IL2 stimulates the proliferation of activated T cells and promotes the secretion of cytokines from monocytes and NK cells. The main biologic consequence of IL2 stimulation is ...