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By John Pastor

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, Ph.D., 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, Ph.D., 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 in.

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, Ph.D., 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."

UF's Mark Atkinson strives to pilot diabetes research to perfect landing

By Melanie Fridl Ross GAINESVILLE, Fla. - University of Florida scientist Mark Atkinson, Ph.D., has logged half a million miles on Delta Airlines. That's a lot of peanuts. Some weeks the diabetes researcher spends more time in the air than in his own laboratory at the UF Health Science Center. On a recent flight he sped over the Atlantic, touching down in the United Kingdom for a scientific meeting in Cambridge, England. Then it was back to Gainesville for a day before racing down the runway yet again, this time stopping in Hershey, Pa., and New York City. Although his rigorous travel schedule takes him physically out of the lab, he admits the chance to reflect is not without its advantages. Once the jet reaches cruising altitude, Atkinson, a pathologist by training, rarely tilts his seat back for a snooze. Instead, he sifts through piles of scientific articles or powers up his tray-sized laptop computer and gets to work. All those efforts have translated into some key findings that are changing the field and quite possibly the future of patient care. And this month they're earning Atkinson two of the world's top honors for diabetes research. "Dr. Atkinson is one of the rare individuals who sees the big picture, from genetics and DNA to bench-side and clinical application," according to a statement from the American Diabetes Association, which selected him to receive its 2004 Outstanding Scientific Achievement Award, sponsored by Eli Lilly and Co. "He has helped the cause of diabetes at many levels, working with equal passion in research, patient advocacy and in raising diabetes awareness." The honor, to be presented at the ADA's annual meeting Saturday [June 5] in Orlando, is given to a scientist who has conducted outstanding research in diabetes and who embodies creativity of thought. Atkinson received a medal and $5,000, and delivered the Lilly Lecture - "30 Years of Understanding the Autoimmune Basis for Type 1 Diabetes: Why Can't We Prevent This Disease?" - before more than 10,000 of the meeting's attendees. Atkinson will then travel to Washington, D.C., to receive the Mary Tyler Moore and S. Robert Levine, M.D., Excellence in Clinical Research Award on June 10, given by the Juvenile Diabetes Research Foundation International for contributions to the clinical translation of diabetes research. "We've been trying to identify Ph.D. investigators who epitomize the translation of research to the bedside, and Mark exemplifies this beautifully; he is highly deserving of this award," said physician Richard Insel, the JDRF's executive vice president of research. "Mark has that unique ability to immediately think about the translation of basic science research and he keeps his eyes on the big picture. I think he exemplifies exactly what you'd want to see in a Ph.D. who is conducting biomedical research. He goes beyond the day-to-day basic science results and thinks about the clinical applications. He's always focused on how he can apply his biomedical research to the bedside." When Atkinson began his career 17 years ago, the study of diabetes immunology was still in its infancy. Fresh out of a graduate program in pathology at UF's College of Medicine, he was among the first to show that administering insulin to mice genetically destined to develop diabetes could thwart the errant immune system's battle to destroy insulin-producing cells in the pancreas. His published findings helped pave the way for the massive National Institutes of Health Diabetes Prevention Trial, which tested the approach in humans. He also was one of the earliest investigators of glutamic acid decarboxylase, or GAD, an enzyme generated by the insulin-producing islet cells of the pancreas. Patients with type 1 diabetes often develop autoantibodies to GAD as the immune system turns against the body's islet cells. Atkinson then helped develop a standardized way to use the presence of these GAD autoantibodies to predict diabetes. According to the ADA, the UF group is recognized as one of the major centers in screening for type 1 diabetes susceptibility in the world. GAD has since been licensed to a company that is developing an experimental drug designed to inhibit progression of type 1 diabetes in people. It's currently undergoing testing, but studies to date show the drug appears to improve insulin production. Atkinson, now the Sebastian family eminent scholar in UF's department of pathology, immunology and laboratory medicine, has spent most of the past two decades building an internationally regarded research program on the immunology of type 1 diabetes. He and his colleagues have extensively studied how to prevent and predict type 1 diabetes. They scrutinized the genetics of the disease. They launched newborn screening programs so treatment could be initiated earlier. Then, about four years ago, they shifted focus, greatly expanding their research emphasis, buoyed in part by a $10.4 million grant from the Juvenile Diabetes Research Foundation International to establish the JDRF Gene Therapy Center for the Prevention of Diabetes and Its Complications at the University of Florida and the University of Miami. UF scientists affiliated with the center, which Atkinson directs, have been studying gene therapy's potential to deliver medicine in novel ways. They also are seeking to engineer rejection-proof tissues for islet and kidney transplant and expand existing efforts aimed at tackling diabetes-associated complications such as vision loss. Meanwhile, as obesity and diabetes near epidemic levels, Atkinson also is studying the role the weight-regulating hormone leptin may play in the development of diabetes. Atkinson has contributed numerous research papers to the scientific literature and was the fifth most-cited author in the field of type 1 and type 2 diabetes between 1990 and 2001, according to the publisher Thompson ISI. He has been praised for bridging his research interests with a commitment to directly serve patients and their families through advocacy and awareness-raising efforts. He continues to serve in key national leadership positions and is currently chairman of the JDRF's Medical Science Review Committee and a member of the National Institutes of Health Immune Tolerance Network.