San Francisco Free Press - AIDS - November 4, 1994

Cancer Drug Holds Hope Against AIDS

Trials of Hydroxyurea to Begin Soon

By David Perlman
Special to The Free Press

SAN FRANCISCO, Nov. 4, 1994 -- A widely used cancer drug that shows unusual promise in laboratory experiments could offer a unique and entirely new approach to therapy for AIDS, a team of government scientists reported Friday.

Intensive animal trials of the drug are expected to begin in San Francisco within weeks, and carefully controlled human trials should follow quickly, local AIDS experts said.

The researchers, led by Dr. Robert C. Gallo, one of the co-discoverers of the AIDS virus, have found that the well-known compound, called hydroxyurea, can alter the cellular environment of invading AIDS viruses so profoundly that the deadly organisms cannot reproduce themselves in the very cells of the immune system that they infect.

In the past, many hopes from laboratory successes with anti-viral AIDS drugs have been dashed because they later proved ineffective or even toxic in patients. But those once-hopeful drugs -- and even today's anti-virals such as AZT or ddI -- have targeted specific proteins inside the genetic machinery of the virus itself, and those viruses, like insect pests foiling DDT, can quickly develop resistance to the compounds.

The Gallo group, however, has aimed at a radically different target, focusing on the immune system cells that the AIDS virus infects rather than on the virus itself.

In their experiments, the researchers used the cancer drug in combination with the anti-viral drug ddI to inhibit the synthesis of one of the essential proteins in the cells of the human immune system that AIDS viruses infect. The viruses must use the protein in order to multiply and thereby continue their lethal invasion.

Low doses of hydroxyurea, the researchers have discovered, completely block the formation of the crucial enzyme -- called ribonucleotide reductase -- inside human white blood cells and macrophages acutely infected with HIV. Without the ability to exploit that enzyme and thereby to assure their own genetic future, the viral invasion --in the test tube, at least -- comes to a dead end.

A report on the new work is being published Friday in the journal Science.

In San Francisco, the chief of one of the nation's foremost virus research laboratories who is familiar with the experiment said the results called for trials of the drug in animals and human patients as quickly as possible.

The compound has long since been approved for both safety and effectiveness in cancer treatment by the U.S. Food and Drug Administration, and there should be no reason not to gear up for carefully controlled clinical trials in human volunteers, said Dr. Warner C. Greene, director of the Gladstone Institute of Virology and Immunology at San Francisco General Hospital.

Greene, also a professor of medicine at UCSF, suggested that the experiments with hydroxyurea could appropriately lead to human trials at a new "Creative Therapies Program," which UCSF is about to establish in the next few months to test new AIDS treatments as they emerge from basic research.

Dr. Joseph M. McCune, the immunologist who developed the famed "SCID-hu" mice that carry the human immune system in their unique mouse bodies, will head that program, and he told The Free Press on Thursday that he expects to start testing hydroxyurea against HIV in his mice within weeks.

Human trials will follow quickly if the drug proves effective in those tests, he said.

Because hydroxyurea itself can be toxic in the wrong doses, McCune warned that uncontrolled experiments by AIDS patients could prove extremely dangerous and should not be tried before results from careful human trials are completed.

Two laboratories at the National Cancer Institute have collaboratd on the experiments. One is headed by Gallo and the other by Dr. John N. Weinstein, director of the institute's Laboratory of Molecular Pharmacology. The lead author of the Science report is Dr. Franco Lori, a molecular biologist in Gallo's lab.

Hydroxyurea has been used for the past 30 years as chemotherapy for such cancers as melanoma, leukemia and ovarian tumors because it inhibits the synthesis of the genetic material that cancer cells need for their wild growth. Right now the drug is undergoing clinical trials as a possible therapy for sickle cell anemia.

According to the Gallo group, hydroxyurea in AIDS could offer major advantages over other AIDS drugs.

It can diffuse swiftly and widely throughout every type of human tissue, including the cells of the central nervous system, the researchers say. "We predict that this drug will be effective against HIV-1 (the virus strain most prevalent through the world) in these cells, and a promising candidate"for treating such devastating disorders as AIDS dementia.

The drug is only mildly toxic and does not further depress immune systems already weakened by the initial attack of the AIDS virus, according to the scientists.

As cancer treatments have shown, the researchers say, "hydroxurea can be administered for years, and sometimes for decades" when its toxicity is monitored carefully. And when used experimentally along with ddI, the drug is highly effective against HIV at doses 10 to 100 times lower than those used in cancer, the report notes.

Finally, the researchers conclude, their evidence shows that the AIDS virus is unlikely to develop resistance to hydroxyurea. Nor, they say, are "escape mutant" strains of the virus likely to emerge.

Copyright 1994 The Free Press

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