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Psoralen's activity comes to the surface.

Psoralen's activity comes to the surface

A chemical found in celery, figs, limes and parsley has proven an effective treatment for years for psoriasis and, more recently, for a type of cancer known as cutaneous T-cell lymphona. Scientists have long thought that this ultraviolet-activated drug, called psoralen, worked solely by affecting DNA within cell nuclei. But about three years ago, chemical evidence began to suggest that psoralen also acts on several types of cell-surface molecules. Now researchers have added cell-membrane DNA to the list of psoralen targets, and other studies are revealing the importance of protein and lipid cell-surface molecules in the drug's therapeutic effect.

The new research brings scientists closer to developing more effective analogs of the drug to treat psoriasis and cancer, says photobiochemist Francis P. Gasparro of the Yale University School of Medicine. Gasparro and others described their findings last week at a photobiology symposium at Yale.

Physicians have tried to explain psoralen's success against psoriasis by its effect on nuclear DNA -- the mechanism of many cancer drugs. This, they reasoned, could account for the chemical's ability to normalize the multiplication of overly productive epidermal cells, clearing up the scaly and often painful skin lesions of psoriasis. But "if the drug simply worked like classical cancer drugs by [affecting the nucleus], killing rapidly dividing cells, one would expect that all the cells in the epidermis would die," notes Yale's Richard L. Edelson.

Researchers have attempted to invoke the same nuclear explanation for psoralen's effectiveness in a cancer treatment known as photopheresis. But the theory behind photopheresis has been that it stimulates the immune system to recognize and attack lymphoma cells. Thus, it would seem "that the [cell] surface is involved because that's all the immune system sees," Gasparro says. Used in people with cutaneous T-cell lymphoma, this treatment involves removing samples of white blood cells, including T-lymphocytes, from a psoralen-treated patient, then exposing the cells to ultraviolet light and injecting them back into the patient (SN: 2/14/87, p. 101).

Prompted by research from the early 1980s demonstrating that lymphocytes contain DNA bound to proteins on their surfaces, Gasparro, Edelson and their colleagues looked for a surface-DNA psoralen target on fresh human lymphocytes. They treated the cells with ultraviolet-activated psoralen and chemically disrupted their membranes. When they isolated the cells' membrane DNA, the group discovered that psoralen had bound to it. In a second experiment, they verified that such psoralen-DNA complexes also form in intact cells when they found that an antibody that specifically recognizes psoralen-DNA complexes binds to psoralen-treated cells but not to untreated cells.

At the meeting, a separate group presented evidence that psoralen's main site of action resides at a cell-membrane protein receptor. Jeffrey D. Laskin at the Robert Wood Johnson Medical School in Piscataway, N.J., suggests that when psoralen binds the receptor on diseased cells, it chemically normalizes a malfunctioning enzyme important in cell division. In studying this receptor, Laskin and his co-workers have developed some "striking new compounds" that show promise in human tissue culture as future drugs for leukemia as well as for psoriasis and other skin diseases.

Italian researchers say they have shown for the first time in living animals that cell-membrane fatty acids are also important psoralen targets. After applying psoralen to rat skin and separating the lipid, protein and nucleic acid components from epidermal cells, they found the most psoralen bound to the lipid fraction, reports Francesco M. Dall'Acqua of the University of Padova.
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Author:Wickelgren, I.
Publication:Science News
Date:Jul 1, 1989
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