IN a handful of laboratories around the world, scientists are attempting to harness the lethal energy of nature's poisons for medical use.
Using techniques of genetic engineering, researchers are removing the parts of poison molecules that allow them to bind to normal tissue,
IN a handful of laboratories around the world, scientists are attempting to harness the lethal energy of nature's poisons for medical use.
Using techniques of genetic engineering, researchers are removing the parts of poison molecules that allow them to bind to normal tissue, and attaching new fragments that guide the toxin into diseased cells.
While the new treatments have yet to produce significant results in people, researchers hope they may someday be useful against certain cancers, autoimmune disorders and even AIDS.
Physicians have already given low doses of these immunotoxins or toxin conjugates to people with unresponsive ovarian cancer; leukemias, or blood cancers, and lymphomas, or cancers of the immune system. The treatments have been given in early clinical trials intended mostly to learn how to use the drugs safely.
For example, a small experimental group of leukemia patients at the M. D. Anderson Cancer Center in Houston are safely receiving intravenous infusions of modified diphtheria toxin, an otherwise deadly substance. In some cases, even at these low doses, researchers are seeing some tumor destruction.
''We can rearrange these toxins in the lab so that they will bind to tumor cells and leave normal cells alone,'' said Dr. Arthur Frankel of Duke University, who expresses a curious fondness for the lethal chemicals.
''To me, they are like characters in Tolstoy novels, ugly on the outside, but beautiful within,'' he said. ''These toxins are capable of killing with terrifying efficiency. But I believe in my heart there is a beauty on the inside, which we can find if we fiddle.''
In December, the Xoma Corporation of Berkeley, Calif., filed the first new drug application with the Federal Drug Administration, seeking permission to market a toxin conjugate. The F.D.A. is now reviewing the application. The drug is a hybrid of the plant toxin ricin and an antibody that binds to certain cells of the immune system. The immune cells cause a sometimes fatal reaction known as graft-versus-host disease in bone marrow transplants.
Although researchers say it is too soon to claim significant success against disease, they hope this new therapy may, in the next decade, succeed where treatments like chemotherapy and radiation have failed.
''We are a bit stuck with conventional chemotherapy,'' said Dr. Ira Pastin, chief of the laboratory of molecular biology at the National Cancer Institute. ''We really haven't advanced cure rates that much in the past three years.'' The new therapy ''represents a very novel sensible approach,'' he added.
Older treatments attack cells as they divide, offering some success against cancer cells, which divide more rapidly than normal cells. But toxin chimeras should attack tumors more specifically, he said.
Many of the toxins used in these conjugates are derived from bacteria, like pseudomonas, a virulent bacterium that can cause pneumonia, and diphtheria. Others, like the ricin toxin distilled from castor beans, exist in minute amounts in plants. Remarkable Efficiency for Toxins
All of these natural toxins bind to and kill cells with an efficiency that molecules made by humans are unable to match. While it may take a thousand molecules of a normal chemotherapy agent to kill a cell, a single molecule of ricin toxin would suffice, and a few micrograms injected under the skin are enough to kill a human, Dr. Frankel said.
Dr. Frankel became interested in toxins after reading about the assassination of a Bulgarian dissident in 1978. The dissident died after he was stuck in the thigh by an umbrella point in a London crowd. Ricin poison was listed as the cause of death.
''As an oncologist, I was getting angry about losing patients with conventional treatments,'' he said. ''I was looking for the deadliest thing around to get those tumor cells.'' Quantity for quantity, he said, ''these are great killers.''
In the 50's, 60's and 70's, scientists clarified these toxins' molecular structures and functions, clearing the way for many of today's new approaches. The scientists found that whole toxin molecules have three essential parts. One segment binds to the cells that the poison attacks. A second orchestrates the entrance of the large toxin molecule into the cell's interior, and the third destroys the cell's normal machinery. 'Harmless' Toxins
A toxin stripped of its binding segment is a fearsome bark without a bite. Some cells lack binding sites for certain toxins, and for these cells the toxins are harmless. For example, diphtheria toxin molecules do not bind with mouse cells, thus mice are unaffected by this poison.
Thanks to this immunity, mice experimentally afflicted with human tumors can be cured with a single dose of diphtheria toxin, which binds only to the human tumor cells.
''Those tumors just melt away,'' Dr. Pastin said. ''That says to me that if we can get recognition right, this approach ought to work.''
In the early 80's, scientists began trying to cleave the binding por