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Release: Aug. 27, 2001

UI researchers receive $7.7 million program project grant from NCI

IOWA CITY, Iowa -- University of Iowa researchers have been awarded a five-year, $7.7 million program project grant from the National Cancer Institute (NCI) to study oxidative events in cancer therapy.

Oxidation is a natural chemical process that occurs in all cells. However, uncontrolled oxidation is harmful to cells and can kill them. Most anti-cancer treatments, from radiation therapy to chemotherapy, produce oxidative events to kill cancer cells.

"The basic idea behind our grant is that if you understand the oxidative processes that occur in cells, then you may be able to manipulate those processes to get better cancer therapies," said Larry W. Oberley, Ph.D., UI professor of radiation oncology and director of the program project grant.

Free radicals are a type of highly reactive molecule that cause oxidation in cells. Cells generally make proteins, known as antioxidants, that have the ability to "mop up" the harmful free radicals and thus prevent injury. The NCI grant will fund four projects investigating strategies to alter the balances between oxidants and antioxidants in cancer cells to improve cancer treatments.

Oberley will lead one project investigating the use of gene therapy to alter the oxidant balance in cancer cells and thereby enhance the ability of chemotherapy to kill cancer cells while sparing normal cells.

The researchers plan to use gene therapy to increase the amount of manganese superoxide dismutase (MnSOD) in cancer cells. This antioxidant protein produces the oxidant, hydrogen peroxide. The anti-cancer agent BCNU, currently used to treat brain tumors, prevents cells from removing hydrogen peroxide. A combination of MnSOD and BCNU results in an excess of hydrogen peroxide, which kills the cancer cells through oxidation.

"This combination has proved to be a very effective anti-cancer treatment in both tissue models of cancer and in animal models," Oberley said. "We hope to move this work into clinical trials against glioma, a currently untreatable human brain cancer, as soon as we can get a version of the gene therapy agent that is approved for use in humans."

A second related project led by C. Patrick Burns, M.D., UI professor of internal medicine, will investigate how modulating oxidative events in cancer cells can make other commonly used anti-cancer agents work better. Bradley Britigan, M.D., UI professor of internal medicine, and Krzystof J. Reszka, Ph.D., UI adjunct associate professor of radiology, are co-investigators on this project.

Burns also is conducting a small clinical study investigating the effect of fatty acids on free radicals in a small group of patients.

Garry R. Beuttner, Ph.D., UI professor of radiation oncology, will head a third project studying photodynamic therapy (the use of light and light-sensitive drugs) to attack cancer cells. This approach also works through oxidative stress.

A light-sensitive drug, given to the patient, reacts with light (a laser beam directed at the tumor) and produces a reactive molecule called singlet oxygen, which kills cancer cells through oxidation. If the researchers can manipulate the antioxidant balance in tumor cells to inhibit removal of singlet oxygen, the harmful effect of this molecule will be enhanced.

The fourth project to be funded by the NCI grant will be led by Frederick E. Domann, Jr., Ph.D., UI associate professor of radiation oncology, and will explore a relatively new area of research. Domann is investigating how transcription factors are affected by oxidative stress. Transcription factors are molecules that control how and when genes are turned on and off. Changes in these processes can cause or suppress cancer. Oberley believes that this area of basic research will have enormous implications for the future of cancer therapy.

"If we can figure out how to modulate transcription of specific genes with free radicals then we can affect cancer progression and therapy," Oberley said. The oxidation balance is a universal system that governs the health of most cells. A better understanding of the mechanisms of oxidative stress could lead to the ability to either correct the balance and protect cells, or make it worse and kill cells.

In most diseases, where oxidative stress is thought to cause cellular damage, the aim would be to protect cells. Diabetes, aging, neurodegenerative disease, heart attack and stroke are examples of conditions where oxidation may play a role in cellular damage. However, cancer and infectious disease are two cases where the goal would be to kill cells.

"This work is important because the reagents we are developing to treat cancer could potentially be useful in treating all of these other conditions," Oberley said. "It's really exciting when you see something you've made to treat cancer that turns out to have a remarkable effect in, for example, diabetes.

"The University of Iowa has accumulated a huge number of excellent free radical researchers," Oberley said. "Some people have referred to the UI as the Mecca of free radical research. Our project benefits greatly from the strength and depth of expertise at this institution."

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