UF researchers pinpoint unlikely ally in cancer fight

May 26, 2004

GAINESVILLE, Fla. — Physicians may be able to unleash the deadly side of a helpful free radical scavenger in the fight against cancer, say researchers at the University of Florida Health Science Center.

Scientists have slightly changed the molecular structure of a naturally occurring enzyme that protects cells by disarming destructive molecules called free radicals, causing a Jekyll-and-Hyde transformation – the enzyme becomes so efficient at mopping up free radicals that it floods cells with toxic levels of hydrogen peroxide, a naturally occurring chemical in the body that is also used in households as a disinfectant.

If delivered to a tumor through a virus, the enzyme brings a crippling rain of hydrogen peroxide down on the rampaging cancer cells. Scientists at the UF Shands Cancer Center and UF’s Evelyn F. and William L. McKnight Brain Institute have used the technique to slow the growth of human lung cancer tumors in mice, according to a recent article in The Journal of Biological Chemistry.

Although untested in humans, researchers hope targeting tumors with the mutated enzyme in combination with drug and radiation therapies will be lethal to cancer. Nearly 25 percent of all deaths in the United States are because of cancer, according to the National Cancer Institute.

“In a human, you would have to inject the virus in the tumor enough times to infect enough cells to make the tumor shrink and die,” said Harry Nick, a professor of neuroscience, medicine and pediatrics in UF’s College of Medicine. “Alone, maybe that’s not enough. But if you were able to add radiation treatments or chemotherapeutic drugs, which also create free radicals, you would increase the anti-tumor potency of this enzyme.”

Free radicals are unbalanced molecules that have lost electrons, usually through natural processes, such as breathing. The body routinely handles free radicals, and even creates them to fight viruses and bacteria. But these off-kilter molecules attempt to stabilize themselves by stealing electrons from nearby molecules, sometimes creating a storm of highly energized particles that damages cells. They’ve even been implicated as a cause of cancer.

UF Health Science Center researchers examined a naturally occurring antioxidant enzyme known as manganese-superoxide dismutase, which maintains cell health by converting destructive oxygen radicals into less troublesome hydrogen peroxide.

Working with the Scripps Research Institute in San Diego, three-dimensional images of the enzyme’s proteins were generated to obtain structural data at an atomic level. At that point, UF scientists, including lead researcher Christopher A. Davis, changed the enzyme by tinkering with individual amino acids.

One mutation slowed the enzyme’s reaction, possibly reducing its usefulness in cell maintenance. Another mutation – a single swap of the amino acid histidine with arginine – made it work much faster, suggesting it would work well as a free radical scavenger.

However, in the process of cleaning up free radicals at an accelerated rate, the mutated enzyme released poisonous levels of hydrogen peroxide.

“We started with the structure of the enzyme with the thought that we were going to make a better mousetrap, which we did,” Nick said. “But instead of doing what we thought it would do, which would be protective, it killed cells, making it useful from a cancer standpoint. We almost couldn’t study the cells because they died so quickly.”

Researchers observed the toxic effect in cultured human cells and in mice modeling tumor growth. In the mice, scientists infected the tumor cells with a virus that expressed the mutated enzyme, then compared the cells with others infected with a virus carrying the natural enzyme.

“A striking inhibition of tumor growth” was observed in the group infected with the mutated enzyme compared with the animals infected with the normal enzyme or with the virus alone, scientists wrote in the article. But nearby healthy cells were not affected.

The work, which involved a multidisciplinary collaboration of UF scientists from pharmacology, medicine and neuroscience, was funded by the UF Shands Cancer Center and grants from the National Institutes of Health. Scientists say one of the next steps will be to observe in animals how the mutated enzyme works against tumors in combination with traditional cancer treatments.

Similar research is under way at the University of Iowa, where scientists have experimented with the naturally occurring form of the enzyme against tumors.

“We’ve found that over expressing the regular enzyme inhibits tumor growth,” said Larry W. Oberley, director of the Free Radical and Radiation Biology Graduate Program at the University of Iowa. “But we think that the engineered enzyme will work even better against tumors because it upsets the natural balance by producing more hydrogen peroxide than the cell is equipped to handle. Its potential for treatment is wonderful.”