Cancer: Unlocking Cytokine Mysteries

By now it should be evident from my previous articles that cytokines are the key ingredients with regard to the workings of immunotherapy. These simple proteins control the response, or lack of response, depending on how they interact with one another. Extensive research is underway to understand exactly which cytokines provide a certain response and which combinations alter, enhance, or reduce that particular response. That's where I come in as that's one of my current primary focuses in my research. Finding the hidden switches so to speak. There are on and off buttons, but they're not that easy to find with our current level of technology but it is only a matter of time until the key to cytokine mystery is fully unlocked an cancer can be beaten.

One Size Fits All: In Some Cases

I will try to avoid becoming too technical but in so doing, you will have to bear with me if I do use terminologies that send you racing for your medical dictionaries or google search engines. There are common structural features for the interleukins that allow us to group the cytokines into specific families. Over the past few years, progress has been made in cloning the genes for the cytokine receptors and in turn, this has made it possible to identify that there are four principal families of cytokines based on their common structures. Functionally, they can be divided into eight families, these being anti-viral, anti-inflammatory, pro-inflammatory, actual inflammatory, T-cell growth factors, B-cell growth factors, haematopoietic factors and chemotactic factors. Understanding the roles of cytokines in immunity and inflammation has made it possible to use cytokines as treatment therapies of their own accord with the expressed aim of blocking or inhibiting or activating these cytokines in order to achieve maximum effect. It is a wonderful age we live in, as we possess the technology to clone cytokines, recombine them into unique forms of naturally occurring and not so naturally occurring cytokines and delivering them to the targeted area through gene therapy. Both natural and synthetic proteins have been manufactured to interfere with ligand and receptor interactions thus blocking or inactivating cytokine actions.

Selling Cytokines by Function

Targeting inflammatory cytokines has proven to be highly effective in treating autoimmune diseases. Recombinant cytokines are proving highly effective in treating cancers. Recombiant IL-2 is being used directly to increase anti-cancer potentiatiion of therapies. Chiron is marketing their recombinant IL-2 under the name Proleukin as a treatment for renal carcinoma and metastatic melanoma, as well as non-Hddgkin’s Lymphoma. Recombinant IL-11 is used to treat post therapy thrombocytopenia and marketed by Wyeth under the name Neumega, for the treatment of thrombocytopenia, Crohn’s disease and colitis.

Intermune Pharma is marketing their IFN-g in a variety of formats for the treatment of ovarian cancer and chronic granulomatous disease. Roche is marketing IFN-a under the name Roferon-A for Hairy Cell Leukemia, Kaposi’s Sarcoma and chronic myeloid leukemia. Schering-Plough has a similar product slightly modified under the tradename Intron-A and has added malignant myeloma and follicular lymphoma to the list of cancers treated.

Neurocrine Bioscience has combined IL-4 with a toxin from pseudomonas bacteria and has begun clinical trials for malignant glioma and kidney and lung cancers.

Chugai and Roche have collaborated on an anti IL-6 receptor for treatment of myeloma. NCI is in Phase I with their recombinant IL-21 treatment for metastatic melanoma and renal carcinoma.

GSK’s recombinant IL-18 is in Phase II trials for renal carcinoma and lymphoma.

With all the major pharmaceutical players becoming involved, it will not be long until cytokines are sold routinely to treat a variety of illnesses and diseases.

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Monocyte Production of Cytokines

Monocytes are potently triggered to produce cytokines through the innate immune system, using pattern recognition receptors that recognize stereotypic components of pathogens that do not occur on mammalian cells. These receptors, such as a lipopolysaccharide (LPS) receptor, contribute to the ability of the immune system to distinguish pathogens from nonpathogenic proteins to which the immune system may become exposed. The cytokines predominantly produced by monocytes include tumor necrosis factor (TNF), and several interleukin (IL) molecules known as IL-1, IL-6, IL-8, IL-12, IL-15, IL-18, and IL-23. IL-8 is also classified as a chemokine known as CXCL8; it and other chemokines are also secreted by antigen presenting cells.

TH1-like lymphocytes are characterized by their production of IFN-γ and primarily contribute to cellular immunity. TH2-like lymphocytes are characterized by their production of IL-4, IL-5, IL-9, and IL-13 and contribute to humoral and allergic responses. TH3-like lymphocytes have immunosuppressive tendencies and are characterized by their production of IL-10 and TGF-β. It is evident that cytokines are critical controllers of all cell, and subsequently as a result, all tissue, growth, migration, development and differentiation. Thusly, understanding cytokines is key to our understanding cancer itself.

In Conclusion

In many acute and chronic inflammatory diseases in humans, such as hepatitis, rheumatoid arthritis and meningitis, plasma measurements have shown large increases in a broad range of cytokines (Vindenes et al. 1998), and monitoring changes in these levels in, for example, synovial fluid in the case of arthritis (Feldmann et al. 1996), can allow an indirect measure of the progression of the disease in response to therapy or in running its natural course (Simpson et al. 2000). In terms of their use in monitoring toxicity under certain conditions, and depending on the correct choice of cytokine to study, their measurement may be a sensitive indicator of the interaction of the drug/chemical with tissues and organs (Anscher et al. 1998). In other words, if we know which cytokines to look for we cannot only measure the effectiveness of our therapy but have advance warning of any toxicity developing as a result of therapy. As can be seen, cytokines serve multiple purposes in medicine both in diagnosis and treatment and therefore will prove to be a most valuable tool in the fight against Cancer.

Dr. Allen Goldenthal

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