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Inherited genes linked to toxicity of leukemia therapy

Contact: Summer Freeman
summer.freeman@stjude.org
901-495-3061
St. Jude Children’s Research Hospital

St. Jude researchers discover that variations in genes that affect the behavior of leukemia chemotherapy drugs in the body are linked to drug toxicity, a finding that will likely help clinicians predict how patients will respond to specific agents
Investigators at St. Jude Children’s Research Hospital have discovered inherited variations in certain genes that make children with acute lymphoblastic leukemia (ALL) susceptible to the toxic side effects caused by chemotherapy medications. The researchers showed that these variations, called polymorphisms, occur in specific genes known to influence pharmacodynamics (how drugs work in the body and how much drug is needed to have its intended effect).

The findings, made during a study of 240 children, are important because these side effects in ALL can be life-threatening and interrupt delivery of treatment, increasing the risk of relapse. The new insights gained in this study could help individualize ALL chemotherapy according to a patient’s inherited tendencies to develop toxic reactions to specific drugs.

“Such individualized therapy would eliminate the time-consuming trial-and-error approach to finding the right dose for a patient,” said Mary Relling, Pharm.D., chair of the Pharmaceutical Sciences department at St. Jude. “When the results of our findings are translated into routine clinical care, we should see less toxicity among children being treated for ALL.” Relling is senior author of a report of this work that appears in the May 15 issue of “Blood.”

The St. Jude team extracted DNA from healthy white blood cells of patients and looked for 16 polymorphisms previously known to be present in genes linked to drug pharmacodynamics. Using a variety of statistical analyses, the investigators identified links between specific polymorphisms and gastrointestinal, infectious, hepatic (liver), and neurologic toxicities during each phase of treatment. The three treatment phases were induction, the initial phase designed to cause remission of the cancer; consolidation, the follow-up after induction; and consolidation, the final phase to ensure comprehensive elimination of cancer cells.

The study showed that some of the 16 genetic polymorphisms are linked to toxic side effects during more than one treatment phase; and some caused more than one type of toxicity. Certain polymorphisms were linked to the pharmacokinetics of specific drugs— how drugs are absorbed by the body, distributed, chemically modified or broken down and eliminated. Variations in pharmacokinetics can alter the levels of drugs in the body, leading to ineffective or toxic levels in individual patients.

For example, during the induction phase, when a variety of different types of chemotherapy drugs are used, polymorphisms in the two genes that were part of a biochemical pathway that breaks down chemotherapy drugs were linked to gastrointestinal toxicity and infection, respectively. In the consolidation phase, when drugs called antifolates were the main treatment, a folate was linked to gastrointestinal toxicity, as it was during the continuation phase. And in all three phases, one polymorphism was linked to hyperbilirubinemia, or jaundice, partly caused by the drug methotrexate.

“Scientists at St. Jude and elsewhere have dramatically improved survival rates from childhood leukemia, but it’s still challenging to find the right dose for each patient,” said Rochelle Long, Ph.D., director of the National Institutes of Health Pharmacogenetics Research Network. “By finding specific genetic variations linked to how individual patients respond to therapy, this work will make medicines safer and more effective for everyone.”

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Other authors of this work include Shinji Kishi, Cheng Cheng, Deborah French, Deqing Pei, Nobuko Hijiya, Ching-Hon Pui and William Evans (St. Jude); Soma Das and Edwin Cook (University of Chicago); Carmelo Rizzari (University of Milan, Italy), Gary Rosner (M.D. Anderson Cancer Center, Houston) and Tony Frudakis (DNAPrint Genomics, Sarasota, Fla.).

This work was supported in part by the National Cancer Institute; the National Institutes of Health/National Institute of General Medical Sciences Pharmacogenetics Research Network and Database; a Center of Excellence grant from the State of Tennessee and ALSAC.

St. Jude Children’s Research Hospital

St. Jude Children’s Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit http://www.stjude.org.

Global Health Vision

May 11, 2007 Posted by | acute lymphoblastic leukemia, Chemotherapy, Genes, Leukemia, National Cancer Institute, St. Jude Children's Research Hospital | Leave a comment

DNA repair proteins monitored at double-strand break

Contact: Summer Freeman
summer.freeman@stjude.org
901-495-3061
St. Jude Children’s Research Hospital

DNA repair proteins monitored at double-strand break
St. Jude researchers have tracked the movement of the cell’s DNA repair kit proteins as they interact with each other and gather at the site of damage
Investigators at St. Jude Children’s Research Hospital had a molecule’s eye view of the human cell’s DNA repair kit as it assembled on a double-strand break to link together the broken ends. Double-strand breaks are ruptures that cut completely across the twisted, ladder-like structure of DNA, breaking it into two pieces.

Using a technique developed specifically for this project, the St. Jude researchers could determine when repair proteins arrived at or around the DNA break and evaluate its repair—even when particular proteins shifted away from the break to make room for others. A report on this work appears in the May 7 online issue of “Nature Cell Biology.”

The findings are important because disruption of the precise movement of these repair proteins can cause mutations, cell death or cancer, and the ability to track the process so closely will give researchers critical insights into what can go wrong with DNA repair. This could lead to novel ways to make cancer cells more sensitive to therapy by blocking their ability to repair double-stranded breaks caused by chemotherapy or radiation. It could also suggest new strategies for enhancing repair of double-stranded DNA caused by radiation, natural oxidants in food or the body and other toxins that can cause disease and aging.

“Prior to this work, there was no practical and efficient way to find and study the DNA repair proteins that organize themselves on and around a double-strand break in human cells,” said Michael Kastan, M.D., Ph.D., St. Jude Cancer Center director. “Our approach solved that problem and allowed us to document the cell’s response to double-strand DNA breaks over time. The technique provides significantly more information about the proteins that repair DNA than is possible using the standard microscope-based approach previously used for such work.” Kastan is the paper’s senior author.

A deficiency in two of these repair proteins, ATM and NBS1, leads to defects in double-strand break repair by disrupting the signaling processes triggered by the break. “A lack of functioning ATM causes ataxia-teleangiectasia, a disease that causes a variety of debilitating problems, such as neurodegeneration, cancer and sensitivity to irradiation leading to double-strand breaks that are not repaired,” Kastan said. “And a lack of NBS1 causes Nijmegen breakage syndrome, another disease that leaves its victims at high risk for cancer and higher sensitivity to DNA-damaging radiation. So this work has important medical implications for these and other diseases linked to disruption of double-strand break repair.”

The assay, developed by Elijahu Berkovich, Ph.D., in Kastan’s laboratory, demonstrates how key repair proteins, such as ATM, NBS1, XRCC4 and gamma-H2AX, interact to coordinate repair of double-strand breaks. For example, the investigators showed that NBS1 recruits ATM to the break; and that ATM and NBS1 cooperate to disrupt nucleosomes—the compact packages formed when strands of DNA wind around proteins, called histones, like thread around a spool. Disruption of the nucleosome at the site of a double-strand break allows the DNA to unravel and expose the area to repair proteins; the loss of functioning ATM and NBS1 blocks this important process. The team also showed that both NBS1 and ATM are needed to ensure that the repair factor, XRCC4, arrives at the double-strand break to help repair the damage.

In addition, the investigators showed that ATM initially binds to DNA both at the site of the break as well as on each side of it. However, XRCC4 later takes the place of ATM molecules at the break while the ATM molecules on either side of the break stay in place. The researchers suggested that ATM had been displaced or moved so that the repair proteins could gain access to the damaged DNA site.

The findings also suggested that before ATM can move to the double-strand break, it must first become activated so it can trigger a critical series of signals linked to DNA repair. Inactive ATM exists as a pair of these molecules linked together. Kastan previously reported in the journal Nature how the inactive ATM molecules separate from each other in response to a double-strand break (http://www.stjude.org/media/0,2561,453_5484_3126,00.html).

To control when and where the double-strand breaks occurred during the study, the researchers used an enzyme called I-PpoI, which naturally seeks certain DNA areas to cut. The investigators modified I-PpoI so that they could better control when the enzyme moves into the nucleus and cleaves the DNA. The team then used a biochemical technique called chromatin immunoprecipitation to collect and identify repair proteins and show where each one bound to the DNA.

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The other author of this article is Raymond Monnat, M.D. (University of Washington).

This work was supported in part by the National Institutes of Health and ALSAC.

St. Jude Children’s Research Hospital

St. Jude Children’s Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit http://www.stjude.org.

Global Health Vision

May 10, 2007 Posted by | Global, Global News, St. Jude Children's Research Hospital | Leave a comment