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MD ANDERSON ONCOL Volume 39, Number 4 (Oct-Dec 1994)
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Date Posted: Thu, September 19 2002, 10:31:40 PDT
Interferon: The Evolution of a Biological Therapy
Taking a new look at cytokine biology
By Kathryn L. Hale
When interferon was discovered in 1957, it was hailed as a significant antiviral agent. In the late 1970s, interferon made a big splash as a symbol of recombinant gene technology and the medical breakthroughs it would bring. Fifteen years later, interferon is a symbol of something quite different--the complexity of the biological processes of cancer and the value of endurance and persistence in tackling this complexity.
Jordan Gutterman, M.D., chairman of the Department of Clinical Immunology and Biological Therapy, The University of Texas M. D. Anderson Cancer Center, was one of the foremost experts on the then little-known interferon when it became an "overnight sensation" in 1980 as one of the first proteins to be produced by recombinant gene technology. Having witnessed the evolution of interferon's status, Gutterman has seen firsthand how progress in the understanding of cancer biology comes not through big breakthroughs but through the steady accumulation of discoveries. Recalled Gutterman, "In 1980, the public perception of interferon was as a big breakthrough, but it wasn't a sudden thing. It was merely one event in the long process of learning everything we can about the protein's role in cancer so that we can determine its clinical applications. It is this steady progress toward elucidation that is exciting and leads to innovation. Discovery is only the first step--development is a much more deliberate, long- term endeavor.
"Interferon wasn't approved by the U.S. Food and Drug Administration for clinical use until 1986, nearly 30 years after its discovery. Because of the expense and duration of the drug development process, fewer anticancer agents will be developed for the clinic in the future. To help us choose the drugs with the greatest potential, we need to improve our understanding of the underlying physiological events leading to cancer."
Gutterman believes that information gained from the study of interferon in the last 15 years has opened the door to a new way of thinking about cancer--as a chronic disease. With a few exceptions, cancers, including the epithelium-derived adult carcinomas, take many years to evolve into a clinically significant entity. Gutterman compares these cancers with cardiovascular disease: both have early signs that, if detected and corrected, may prevent serious disease later on. "Although the biology of the two appear unrelated, they have subtle similarities; furthermore, both begin with a clinically undetectable genetic defect that causes progressive damage and leads over 20 or 30 years to a serious, even fatal, medical condition. Like cardiovascular disease, cancer is exacerbated by environmental factors, which accelerate the rate of conversion of the altered or damaged cells to malignancy." Furthermore, the similarities between the two are the key to early detection of cancer: Gutterman foresees a method of measuring early signs of cancer, that is, the abnormal genes, as blood pressure measurement now detects the early signs of cardiovascular disease.
The abnormal genes that cause cancer comprise at least three types: oncogenes, which, when altered, encourage the abnormal growth and division that characterize cancer; tumor suppressor genes, which, when altered, fail to control this abnormal growth and division; and the newly discovered DNA repair genes, which, when altered, fail to repair mutations that can lead to cancer. Researchers believe that there are about 30 to 40 tumor suppressor genes in the body, each of which produces a protein, and they are starting to believe that these proteins are controlled by "master" tumor suppressor proteins such as Rb (for retinoblastoma, with which it was first associated) and p53 (associated with many different tumors). Evidence from the laboratory suggests that returning just one of these tumor suppressor genes to its normal function can appreciably reduce the aggressiveness of the malignancy if not stop the growth.
Gutterman became intrigued by interferon when it was discovered to inhibit cell growth; it was also known to have certain positive effects on the immune system. He now considers it analogous to a tumor suppressor protein: it inhibits the growth of cells, particularly malignant cells, it blocks the effects of many oncogenes and growth factors, and unlike other biological agents, it inhibits cell motility (cell motility is critical to the process of metastasis). Gutterman suspects that this inhibition of cell motility is at least as important as the inhibition of cell growth in stopping the growth of cancer.
Cells are embedded in the extracellular matrix, which comprises fluids, proteins, micromolecules, and other substances around the cells and allows the cells to communicate with each other. Controlling this communication are cytokines, which are secreted by cells into the plasma and extracellular matrix. They work rather like a neighborhood cop (in Gutterman's words) to keep the cells and their extracellular environment in a balanced, homeostatic state.
Intercellular communication is dependent on the proper functioning of all the structural components of the tissue through which the messages are conveyed: the matrix, the cell membrane, the cytoskeleton, and the cell itself. In cancer, the communication network between cells is disrupted. If the cytoskeleton is disrupted, the messages don't get through to the nucleus and the nucleus begins to function abnormally. Since the nucleus is the site where the oncogenes or tumor suppressor genes get switched on or off, this abnormal functioning can lead to malignancy. When this happens, the cells start growing irregularly and do not differentiate. They may start to move and disrupt other cells. Gutterman believes that interferon, probably in concert with other extracellular and cellular substances, restores the balance, the homeostasis, making sure the messages get through properly. It stops growth, stops motility, and enhances the ability of the cell, through adhesion molecules, to respond to its environment. It corrects defects, injuries, in the cytoskeleton. Interferon has also been found to block angiogenesis, the initial step in the formation of new blood vessels that is essential to the growth of malignancies. Moreover, it blocks fibrosis, a response to injury that stimulates many different kinds of cells and promotes cell growth.
Traditional chemotherapy has taken the approach of interrupting the functioning of cells, especially division, with little attention to the surrounding structures. The success of this strategy in most cancers may have been limited, suggested Gutterman, because it does not address this disruption of the extracellular environment.
Tumor suppressor proteins Rb and p53 work within the cell to regulate the cell cycle. Interferon, working outside the cell, is believed to induce and regulate Rb (its relationship with p53 is not well understood). Gutterman believes that interferon may, in concert with the tumor suppressor proteins inside the cell, mediate the tumor suppressor function, and that the protein inside the cell cannot be totally effective without adequate interferon outside the cell. He speculates that attempts to stop cancer by replacing defective tumor suppressor genes with functioning genes that will produce the effective tumor suppressor protein in the cells might be successful only if extracellular levels of proteins such as interferon are adequate.
Although aging and certain environmental insults such as cigarette smoking may deplete interferon levels, inadequate levels of interferon cannot be remedied by simply administering the protein to the body. For one thing, interferon is toxic in pharmacologic doses. Fortunately, technology can provide solutions: interferon can be administered in tiny physiologic doses that are effective but not toxic; interferon analogues can be synthesized that suppress tumor growth without toxic effects; or endogenous production of interferon can be induced or increased by gene therapy. For this reason, Gutterman sees cytokine biology as an important emerging field. He is quick to say that he does not see interferon as a cure-all for cancer, but that the way researchers are looking at the protein is changing: "We are asking totally different questions than we did 15 years ago."
Chemoprevention of cancer may be one application of interferon if the problems with toxicity and route of administration can be solved. Only oral agents are feasible for large population-based chemoprevention trials, and right now interferon is administered only by injection. One form of interferon, interferon-alpha, has been used in a few studies in conjunction with retinoids, naturally occurring and synthetic analogues of vitamin A that are known to have inhibitory effects on cancer development. The results were encouraging in that interferon did appear to have a potentiating effect on the retinoids.
Interferon is in a period of transition. Gutterman believes that cancer researchers are going to have to start looking at new ways of treating cancers and assessing what constitutes an effective drug. His work has indicated that interferon is not effective in advanced cancers. If he'd been discouraged and stopped there, he never would have learned that the protein can be very effective in very early stage disease. He says that we will have to change the way we think about biological agents: biologicals and chemotherapy are very different approaches and should not be evaluated in the same ways. They may be effective in stopping or stabilizing cancers, not in shrinking large tumors.
Gutterman is especially excited about two areas of research now active at M. D. Anderson. One is the search for inhibitors of angiogenesis; one of the most promising is a fungus called fumagillin, which has the potential to act synergistically with interferon, limiting the proliferation of tumor cells. The combination is being tried in patients with prostate cancer, but the studies are still at very early stages. The other area, the combination of interferon with replacement of abnormal tumor suppressor genes, is still in the laboratory, although the researchers hope to have a clinical protocol under development soon. This reflects the new way of thinking of interferon as an extracellular tumor suppressor protein. It is probable that interferon will not work to suppress tumors on its own, but will be used with the replaced tumor suppressor protein in place to inhibit tumor growth. "Interferon is just one piece of the whole tumor suppression puzzle," affirmed Gutterman.
Gutterman believes that the interrelationship of carcinogenesis, angiogenesis, and fibrosis in cancer development suggests that cancer is the result of an injury to tissues or cells. In the way the body responds to them, tumors are in some ways very like wounds, and interferon heals them: it stops the cells from moving around, it stops the fibrosis, it stops the blood vessels, it stops the growth. Gutterman feels certain that, given time, we will be able to harness these qualities and use them to stop the growth of cancer.
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Physicians who desire more information may write to Dr. Gutterman, Department of Clinical Immunology and Biological Therapy, Box 41, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030, or call (713) 792-2676.
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For the first of the series of two articles on biological therapies, see Biological Response Modifiers Promising Adjuvants to Cancer Therapy (April-June 1994).
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M. D. ANDERSON ONCOLOG
Volume 39, Number 4 (October-December 1994)
Copyright 1994 The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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