Nuclear therapy used to fight tough germs

NEW YORK, Aug. 25 (UPI) -- Researchers have discovered lashing radioactive atoms to microbe-hunting proteins could kill germs considered impervious to all other medical therapies.

The work represents the first time anyone has experimented with radiation to combat infectious diseases and there is excitement among scientists and physicians that it has the potential to solve the increasing problem of antibiotic resistance as well as lead to novel ways of treating biological weapons and infectious diseases, such as AIDS.

In addition, researchers suggest this strategy could help destroy quickly viruses, bacteria and parasites against which no drugs exist, such as SARS, Ebola or even new plagues doctors have not yet faced.

"With biological weapons, new strains could be very easily engineered, and against them there are no existing treatments," researcher Ekaterina Dadachova, a radiochemist at the Albert Einstein College of Medicine in the Bronx, N.Y., told United Press International. "In this climate, we need something new and efficient."

Dadachova said radioactive drugs could help save the lives of the many organ transplant patients, prematurely born children, AIDS patients and others living with weakened immune systems. Infections attacking these patients often resist standard drugs.

"Some 50 percent of all heart transplant patients die of fungal infections that cannot be treated, because their immune systems were completely suppressed so the donated hear can be accepted by the body," Dadachova explained.

Since recorded history, mankind has employed medicines to save lives against disease, spawning the multi-billion-dollar pharmaceutical industry in the modern era. As the drug industry evolved, however, drug-makers increasingly have had to struggle against the force of natural evolution. Though a manufactured chemical might kill nearly all of the billions of germs that can infest an individual, random mutations over time can lead to organisms that are resistant against that chemical.

As resistance increases, doctors are forced into less-attractive options, such as increasing the dose, which can lead to greater expense or dangerous side effects. In the end, health officials must give up on a drug altogether, relying on backup drugs that often prove more expensive, which often puts them out of the reach of developing nations struggling with killers such as malaria, tuberculosis and HIV that the World Health Organization has warned are growing tougher every day.

"When resistance against (emergency drugs used to treat these diseases) also emerges, the world will run out of treatment options," the WHO said in a written statement.

That is one reason the medical research community is excited about the prospect of treatments based on radiation, which has been used routinely for 30 years to kill microbes and parasites and to sterilize medical implants and surgical instruments. Likewise, fruit leaving Hawaii and Florida are irradiated. In both cases, high-energy light beams such as gamma rays are used, and do not transfer radioactivity to their targets.

Radiation also has been used to treat cancer by killing tumorous cells, though radiation can kill healthy tissue as well. Instead of using machines to blast germs inside a body with radiation that could damage surrounding cells, however, Dadachova and her team created a far more specific radiation therapy by stick radioactive specks onto antibodies.

Antibodies are the high-powered sniping rifles of the body's personal defense arsenal. Each of these complex proteins is tailor-made by the immune system for every intruder the body comes across. They are programmed to clamp down on and neutralize enemies. Dadachova's idea essentially employs a precision missile like an antibody and chemically straps on a more potent warhead -- in this case radioactive atoms.

"It's a very novel concept. Radiation has not been applied to infection before," nuclear medicine physician Christopher Palestro of Long Island Jewish Medical Center of New Hyde Park, N.Y., told UPI. "This is an entirely new field that has not been explored."

Dadachova and Einstein colleague Arturo Casadevall, an immunologist and microbiologist, decided on the life-threatening fungus Cryptococcus neoformans as their target. The infection is found in 6 percent to 8 percent of AIDS patients, but current antifungal drugs often are ineffective in patients with weakened immune systems. The fungus is by now a familiar enemy of doctors and medical scientists have for years been able to use antibodies that latch onto it.

The researchers used radioactive isotopes rhenium-188 and bismuth-213, both of which are finding use in anti-cancer therapies or experiments. Unlike stable atoms, radioactive isotopes possess abnormal numbers of neutrons, and when they decay into smaller, more stable atoms, they release energy. Both rhenium-188 and bismuth-213 decay rapidly -- a matter of minutes or hours, respectively -- so even when they are excreted from the body, they pose no radiation threat to the environment.

The researchers studied how C. neoformans attacked mice with weakened immune systems. After each rodent was infected intravenously with about 10,000 fungus cells, the organism multiplied into roughly 400 million cells. The scientists noted a 30-millionth-to-50-millionth-of-a-gram dose of their novel antibodies were enough to deliver a radioactive atom to every one of those fungus cells in the infected mice.

In findings appearing in the Proceedings of the National Academy of Sciences, Dadachova reveals mice with weakened immune systems benefited from just one dose of the radioactive antibodies. Nearly all of the fungus cells were killed, while mice with weakened immune systems that did not receive the radioactive-enhanced drugs died within two or three weeks of infection.

"I look at this as tactical nuclear therapy, TNT," said infectious disease specialist Tom Walsh of the National Institutes of Health in Bethesda, Md. "It's very exciting, and represents the beginning of what could be a very novel approach to the growing threat of antibiotic-resistant bacteria."

Dadachova said the prospects for successful treatment with radioactive drugs is doubly encouraging because "the amount of radioactivity used is trivial. The amount is actually less than patients receive for routine treatment of thyroid cancer, which doctors have used for 50 years."

She stressed rhenium-188 and bismuth-213 are nowhere as toxic as plutonium, the most publicly feared radioactive substance. "Bismuth-213 lives for 46 minutes, and rhenium-188 for 17 hours. Plutonium lives for thousands of years. There is no comparison," she explained.

NIH chemist Martin Brechbiel found the work "lovely. I would like to see this followed up with expanded studies in higher animals and, if justified, carried further," he said.

Brechbiel cautioned, however, that radioactive isotopes might prove both expensive and in short supply. Dadachova concurred, noting the U.S. Department of Energy was selling bismuth-213 at $1,500 for trillionths of a gram or less.

"Here in the United States, the supply of radioisotopes is concentrated in the hands of the Department of Energy. Whatever their current policies, that will affect price," Dadachova said. She explained she received her supply of bismuth-213 free as a donation from the Institute of Transuranium Elements in Germany. Still, she said she hopes future therapies can switch from research-grade radioisotopes to cheaper, commercial-grade ones.

Dadachova added if radioactive drugs are ever deployed against infections, they likely would be used only in emergencies. "This treatment is not designed to be used routinely against infections existing drugs can treat," she said.

The scientists hope to bring germ-fighting radioactive drugs to clinical trials in perhaps a year and a half or two years. They currently are moving beyond fighting fungi in their research. "We are already trying to treat bacterial infections, and have completed experiments," Dadachova said. "Our ultimate goal is to try it for viral diseases, which are the most difficult to treat. We would like to treat HIV. If this could work, this would be very encouraging."