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St. Jude Study Finds Treatment With New Drug Might Make Tumor Cells More Sensitive to Therapy

Wednesday, September 17, 2008 General News J E 4
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Study shows treatment with a newly discovered drug could be useful in sensitizing tumor cells to therapeutic irradiation and potentially some chemotherapies



MEMPHIS, Tenn., Sept. 16 /PRNewswire-USNewswire/ -- Scientists at St. Jude Children's Research Hospital have shown that it might be possible to make tumor cells more sensitive to irradiation and some types of chemotherapy by treating them with a drug that cripples their ability to repair DNA damage caused by these therapies.



The St. Jude researchers demonstrated in the laboratory that a molecule called CP466722 rapidly blocks the ATM protein's ability to orchestrate a series of biochemical events that culminate in the repair of DNA damaged by irradiation. The molecule exerted its effect in small quantities, and its effects rapidly ended after it was removed from cells, suggesting that such a treatment in humans would not have significant or long-term side effects, the researchers said.



Results of the study were published in the Sept. 15 issue of the journal Cancer Research.



ATM plays a critical role in repairing a type of DNA damage called double-strand breaks, in which each of the two strands making up this molecule are cut, according to Michael Kastan, M.D., Ph.D., director of the St. Jude Comprehensive Cancer Center. This process protects cells from the potentially lethal or mutation-causing effects of free oxygen radicals and irradiation--both of which routinely threaten them, he added. Kastan is senior author of the report on these findings.



Children lacking the gene for ATM develop ataxia-teleangiectasia, a disease that causes several debilitating problems, such as neurodegeneration, cancer and sensitivity to irradiation that leads to irreparable, double-stranded DNA breaks.



"We found that inhibition of ATM activity with CP466722 produces cellular effects that are identical to those seen in cells that lack ATM," Kastan said. "It's as if we temporarily turned 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 lab
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