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TUMOR NECROSIS FACTOR
from the book CANCER THERAPY
© 1992 by Ralph W. Moss, Ph.D.
Tumor necrosis factor (TNF) is one in a family of natural chemicals with powerful anticancer properties. These chemicals were first created by pretreating mice with the immune stimulant BCG and then giving them endotoxins, a substance found on the cell walls of bacteria.
The blood serum from such animals then contains a factor that causes dramatic, overnight "necrosis" or death of tumors. Scientists thus called this tumor necrosis factor (TNF). It is probably released from macrophages (1).
This 1975 discovery was ultimately derived from the work of Dr. William B. Coley (Coley's toxins) who noted that bacterial infections could cause the regression of tumors. TNF is a regulator of both inflammation and immunity and is presently in clinical trials as an anticancer drug at a number of centers (2, 3).
TNF-or rather the TNFs, for this is turning out to be a class of chemicals-are thus a group of proteins that are able to destroy tumor cells. They naturally occur in the body in small amounts, but now can be manufactured by recombinant DNA technology. While the results in animals have been dramatic, it is questionable whether they will show the same degree of response in humans. One problem is that TNFs, as powerful foreign proteins, can cause serious dose-limiting toxicity in people, including malaise and flu-like symptoms. Such side efects are similar to that seen with Coley's toxins, however, and probably do not lead to long-term damage to the immune system, such as is seen with conventional chemotherapy.
The treatment of cells with TNF or interferon results in "an antiviral state" and in the production of a common set of proteins. In fact, the induction by TNF is mediated through mechanisms that are both dependent and independent of interferon (4).
Tumor cells from 102 patients were exposed in the test tube to TNF, made by recombinant technology. Sixty-eight of these were also tested against interferon-gamma, also made by recombinant means.
Adding interferon-gamma reduced the dose of TNF required for significant antitumor activity "by about threefold." Based on such observations, scientists at the Arizona Cancer Center in Tucson concluded that recombinant TNF warrants more advanced clinical trials in selected solid tumors, with an emphasis on colorectal and lung cancer. They also felt that combining TNF and interferon-gamma should be studied in endometrial and breast cancer (5).
Japanese scientists have investigated the combined effects of TNF with lentinan (a mushroom polysaccharide) and lipopolysaccharide (LPS). They found that when LPS was administered after the tumor had grown fairly large, hemorrhagic (bloody) necrosis of the tumor occurred within 48 hours. They called this a "high antitumor effect."
When TNF was administered to cancer-bearing mice, bloody necrosis of the tumor was also observed within 48 hours. There was a better antitumor effect compared to LPS alone. But when LPS was used with lentinan "the highest antitumor effect could be achieved" (6).
Certain immune boosters perform better when used against tumors from patients who had previously been treated with chemotherapy, researchers at Oncotech, Inc. wrote in JNCI. These include women who had responded to treatment of breast and ovary cancers. These agents include TNF, interferon gamma and ImuVert, but not IL-2 or interferon alpha. The Irvine, CA scientists speculate that a successful response to chemotherapy "produces massive release and processing of tumor antigens." This in turn leads to a state in which the human immune system is primed to respond to such innovative drugs with "potent, specific antitumor effects" (7).
1. Oettgen HF, et al. Endotoxin-induced tumor necrosis factor. Recent Results Cancer Res.1980;75:207-12.
2. Old LJ. Tumour necrosis factor. Another chapter in the long history of endotoxin. Nature.1987;330:602-3.
3. Old LJ. Tumor necrosis factor. Sci Am.1988;258:59-60.
4. Rubin BY, et al. Tumor necrosis factor and IFN induce a common set of proteins. J Immunol.1988;141:1180-4.
5. Salmon SE, et al. Antineoplastic effects of tumor necrosis factor alone and in combination with gamma-interferon on tumor biopsies in clonogenic assay. J Clin Oncol.1987;5:1816-21.
6. Moriya N, et al. [Antitumor effect of bacterial lipopolysaccharide (LPS) and a combination use of LPS and lentinan on C3H/He mice bearing MH-134 tumor]. Gan To Kagaku Ryoho.1983;10:1646-52.
7. Weisenthal LM, et al. Effect of prior cancer chemotherapy on human tumor-specific cytotoxicity in vitro in response to immunopotentiating biologic response modifiers. J Natl Cancer Inst.1991;83:37-42.