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St. Jude Study Finds Treatment With New Drug Might Make Tumor Cells More Sensitive to Therapy
Date:9/16/2008

ed normal cells into cells indistinguishable from those of children with ataxia-teleangiectasia."

The protective role of ATM makes it a tempting target for researchers looking for a way to prevent cancer cells from repairing DNA damage caused by therapeutic irradiation, Kastan noted.

Previously Kastan's team found how ATM is activated by a signal from damaged DNA only seconds after the damage occurs. The activated ATM, in turn, activates other proteins by attaching a molecule called phosphate to them in a process called phosphorylation. This sets off a cascade of biochemical reactions that amplifies the initial ATM response leading to repair of the double-stranded break.

"Our ability to rapidly and reversibly regulate ATM activity with CP466722 also gives us a new tool to study the function of this protein, which plays such a critical role in the ability of both normal and cancerous cells to repair their DNA," said Michael Rainey, Ph.D., a postdoctoral fellow in the St. Jude Department of Oncology. "This approach will help us learn more about the repair events triggered by ATM in response to DNA damage." Rainey is the report's first author.

Kastan also noted that CP466722 provides his team with a basic chemical structure that they can build upon as they try to modify the molecule to enhance its potency and specificity and move studies from isolated cells to mouse models.

"Results of those mouse model studies would help us to determine if and how to proceed with studies in patients with cancer," Kastan said.

The St. Jude researchers demonstrated in isolated cells that irradiation activated ATM, which in turn triggered the normal cascade of biochemical events that repaired broken DNA, and that CP466722 inhibited all of these events. This occurred not only in standard laboratory cells called HeLa cells, but also in human breast cancer cells. Overall, the response to CP466722 in irradiated cells was similar to that seen in cel
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SOURCE St. Jude Children's Research Hospital
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