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Toward a 'magic bullet' for melanoma.

The potent toxin that causes diphtheria is now being targeted against malignant cells to provide a potentially powerful weapon against melanoma, an often deadly form of cancer. John R. Murphy of Boston University Medical Center described his unpublished results this week in Bethesda, Md., at the meeting of the National Institutes of Health Recombinant DNA Advisory Committee (RAC).

Murphy and his colleagues have produced a hybrid protein that is a modified diphtheria toxin. The new protein remains a potent killer of cells, but through protein engineering (see p. 204) the scientists have altered its target selection. They removed the part of the gene responsible for the binding of toxin to diphtheria-sensitive cells and attached a synthetic gene for a hormone called alpha-melanocyte stimulating hormone (MSH). Receptors for MSH occur on skin cells called melanocytes. When these cells grow unchecked, malignant melanoma results.

The hybrid gene was moved into the laboratory bacterium Escherichia coli to produce hybrid protein. Murphy reports that this remodeled toxin kills human malignant melanoma cells growing in laboratory culture. Yet the protein does not harm other laboratory-grown cells that are very sensitive to diphtheria toxin but lack MSH receptors. In fact, Murphy and his colleagues found that injecting guinea pigs with a dose 1,000 times the lethal dose of diphtheria toxin caused no observable ill effects.

While much testing remains to be done before such a hybrid toxin is used clinically, the scientists on RAC are enthusiastic. "This is a real triumph for molecular biology," says Bernard Davis of Harvard Medical School. "It's [a] 'magic bullet' with a vengeance."

Next, Murphy plans to construct another hybrid protein, a diphtheria toxin that binds to receptors for interleukin-2 on white blood cell membranes. This chimeric toxin is expected to be useful for killing the activated T cells responsible for rejection of organ transplants as well as for certain forms of elukemia and autoimmune desease. RAC unanimously approved the proposed research with a moderately stringent level of safety requirements.
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Author:Miller, Julie Ann
Publication:Science News
Date:Sep 28, 1985
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