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ATM Kinase Inhibition Increases Cellular Sensitivity to Radiation Treatment

By LabMedica International staff writers
Posted on 14 Jun 2010
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Treatment of cancer cells that inhibits the enzyme ATM kinase renders them more sensitive to radiation treatment while having little effect on normal cells.

Ataxia telangiectasia mutated (ATM) is a serine/threonine-specific protein kinase that is recruited and activated by DNA double-strand breaks. It phosphorylates several key proteins that initiate activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair, or apoptosis. The protein is named for the hereditary neurological disorder Ataxia telangiectasia (A-T), which is caused by mutations of the ATM gene. The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability.

Cells from A-T patients exhibit sensitivity to radiation-induced cellular damage that results in increased chromosome aberrations and cell death (radiosensitivity). Investigators at the University of Pittsburgh School of Medicine (PA, USA) reported in the June 1, 2010, issue of the journal Science Signaling that even transient inhibition of ATM kinase for one hour, initiated 15 minutes after irradiation of A-T fibroblasts, resulted in an accumulation of persistent chromosome aberrations and increased cell death.

"A characteristic symptom of A-T is heightened sensitivity to ionizing radiation, such as X-rays and gamma rays,” said senior author Dr. Christopher Bakkenist, assistant professor of radiation oncology, pharmacology, and chemical biology at the University of Pittsburgh School of Medicine. "If we understand why that happens, then we might be able to reproduce it to make tumor cells vulnerable to radiation treatments while sparing healthy cells, which would make therapy more effective while minimizing side effects.”

"A characteristic of tumor cells is that they rapidly replicate, possibly because they have mutations that encourage cell division or that thwart repair pathways,” said Dr. Bakkenist. "But ATM kinase remains present in the vast majority of human cancers, so that suggests it is needed by those diseased cells during replication. So that would make cancer cells particularly vulnerable to an ATM inhibitor, while healthy cells should be unaffected.”

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University of Pittsburgh School of Medicine


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