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Dentist Sees Breaks in Cells' DNA As Precursor to Cancer

The Philadelphia Inquirer

04-15-05

Knight Ridder Newspapers

(KRT)

PHILADELPHIA - As students cloned DNA samples and heavy metal played over the lab radio, Thanos Halazonetis bent over a microscope in a dark closet at the Wistar Institute, searching for green dots.

With a click of a camera they appeared: tiny pinpoints glowing within cell nuclei. The glow was just a smattering of broken DNA strands, but to the molecular biologist, they signaled the earliest signs yet discovered of cancer to come.

Scientists have long thought that different kinds of cancers carried different warning signs. But in a study featured on the cover of this week's issue of Nature, Halazonetis says they all share the same red flag - broken DNA. If true, doctors might be able to detect cancer before the cells start mutating, and hopefully, develop treatments to attack only the diseased cells.

"Cancer is more than 100 different diseases, and what this group has found is a commonality in early stages of development," said Curtis Harris, a clinical oncologist and molecular biologist at the National Cancer Institute.

Much of the fuss surrounds a gene called p53. The gene releases a protein when the cell is injured or stressed. It causes the cell to stop dividing and to repair itself, or if all else fails, it signals the cell to die.

Since 1989, scientists have known that p53 plays a role in the way cells become cancerous. The theory is that either the cell mutates and destroys p53 altogether, or the gene stops working. Without that gene, the sick cells continue to divide instead of die.

But in his paper, Halazonetis, 45, argues that there is a way to kill a cell without p53. He said the DNA breaks occur only in cancerous or precancerous cells and therefore can be targeted and forced to die with or without p53's intervention.

The former dentist started working on the mystery during his free time while working at Merck & Co. Inc., in 1992.

"At a pharmaceutical company, you don't really get to make basic science discoveries - like what causes cancer," he said.

The following year, he went to Wistar, an independent nonprofit biomedical research institute on the University of Pennsylvania campus. With a $500,000 annual grant from the National Cancer Institute, he started looking at why cells get stressed.

About five years ago, he discovered the connection between the broken DNA strands and a protein called 53BP1. When the DNA breaks, it alerts the protein, much like an accident sets off an air bag in a car.

Scientists had thought that oxygen deprivation or injury kicked p53 into action and began the cell death process. Halazonetis, who examined the cell structure of several kinds of cancer, says they were wrong.

"Everyone knew that damaged DNA alarmed p53 and killed the cell," said Maureen Murphy, a molecular biologist specializing in cell death at the Fox Chase Cancer Center in Philadelphia. "But no one knew that was happening in precancerous cells."

The DNA breaks when the cell starts dividing faster than it should, Halazonetis said. As it splits faster and faster, the DNA replication process can't keep up.

"It's like driving with the parking brake on; sooner or later, the brake is going to break," Halazonetis said.

Once the strands break, the 53BP1 protein is alerted and goes to the gaps in the nucleus. It tries to get the cell to repair the damage and appears as little green dots on the microscope screen.

If the protein were disabled, he said, the cell would not try to repair itself. It would just die.

"If you inhibit the 53BP1 protein, the cancer cell would try to divide with broken DNA, and the cells would die," he said.

Halazonetis hopes his findings might one day change the way cancer is treated and how early. Now radiation and chemotherapy kill off normal cells as well as cancer cells.

If he's right, the DNA breaks and presence of the protein could become a diagnostic marker for doctors, alerting them to precancerous cells for earlier treatment. Then perhaps a medicine could be developed that would kill only cells with broken strands, leaving healthy cells alone.

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