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The dark side of tumor-fighting protein.

A human protein that has been highly touted, in genetically engineered form, as a potential anticancer drug has been found to be essentially identical to another body protein, cachectin, that causes debilitating weight loss in people with chronic infection or cancer. And in a separate study, cachectin is also reported to be a mjor cause of bacterially induced shock.

Reports in the Aug. 30 SCIENCE detail cachectin's role in weight loss through the inhibition of fat storage cells, as well as its role in the onset of shock. The protein's striking similarity to tumor necrosis factor (TNFe, which is nearing U.S. anticancer trials with humans, was reported in the Aug. 8 NATURE.

The fat cell finding was a collaboratin between laboratories at Rockefeller University in New York City and Stanford University. The researchers applied cachectin, with is produced by ifnection-fighting white blood cells, to mature fat cells and found that the cells lost their fat-synthesizing and storage potential. They also observed a reversible decline in the expression of genes that play an active role in the development of fat cells.

Deemphasizing fat storage frees up energy, says Frank Torti, one of the Stanford researchers, who speculates that the protein mobilizes energy to fuel the body's fight against infection or cancer. But when the condition becomes chronic, "what was once a benefit becomes a problem," he says, and the person loses weight even when food intake remains constant.

In the second study, three Rockefeller University researchers injected mice with a bacterial protein that can induce shock. They found they could block the effect by blocking the action of cachectin. "We think it [cachectin] is one of the major causes of shock," says Anthony C. Cerami of Rocketfeller.

"We think if you have small amounts it is good because it mobilizes energy for the immune system," says Cerami. But when the immune system can't get rid of the invader, cachexia -- wasting -- ensues. And in an overwhelming infection, the cachectin causes shock, he says.

Cerami and his colleagues report in NAATURE that human TNF and mouse cachectin are nearly identical; human TNF and human cachectin are completely identical, he says.

Cerami suspects the ability to kill cancer cells is not the factor's major role in the body. "It's probably much more important in facilitating the fight against infection, which is a much more common occurrence," he says.

The work points out potential toxicities in cachectin's twin, TNF, says Torti, "but what's predicted in tissue culture models vis-a-vis what happens to people can be very different." Human trials with TNF have already begun in Japan, and reportedly a slight fever has been the only side effect.

Finding the proper dosage will be key, Cerami says. "Losing weight for one week won't hurt that much," he says. "The limiting factor will be shock."

A spokesperson for Genertech, Inc., in south San francisco says that some animals in their preliminary TNF trials lost weight but gained it back after the study. The company hopes to begin human trials this fall, she says.

Alfred Rudolph, a clinical researcher at Cetus Corp. in Emeryville, Calif., says the cachexia and shock findings don't affect Cetus's plans to develop TNF as an anticancer agent. The company is creating slightly modified versions of the protein and hopes to begin clinical trials in 1986. Eventually, says Rudolph, they may work on the protein as an anti-obesity factor.

Dan Longo of the NAtional Cancer Institute in Bethesda, Md., where clinical trials with TNF could begin in late fall, says that since side effects will be carefully monitored, the reported findings won't affect the clinical trial. The findings, he notes, suggest other ways to use TNF, such as employing an antibody to the protein to prevent shock.
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Title Annotation:tumor necrosis factor similar to cachectin
Author:Silberner, Joanne
Publication:Science News
Date:Aug 31, 1985
Previous Article:Sweethearts resist infection.
Next Article:Researchers identify 'cancer anorexia'.

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