Cancer cells' DNA repair disrupted to increase radiation sensitivity

ScienceDaily (Dec. 1, 2011) — Shortening end caps on chromosomes in human cervical cancer cells disrupts DNA repair signaling, increases the cells' sensitivity to radiation treatment and kills them more quickly, according to a study in Cancer Prevention Research.

Researchers would to like see their laboratory findings -- published in the journal's Dec. 5 print edition -- lead to safer, more effective combination therapies for hard-to-treat pediatric brain cancers like medulloblastoma and high-grade gliomas. To this end, they are starting laboratory tests on brain cancer cells.

"Children with pediatric brain cancers don't have very many options because progress to find new treatments has been limited the last 30 years," said Rachid Drissi, PhD, principal investigator on the study and a researcher in the Division of Oncology at Cincinnati Children's. "The ability to make cancer cells more sensitive to radiation could allow physicians to use lower radiation doses to lessen side effects. Too many children with brain cancer can develop disabilities or die from treatment."

Before treating cells with ionizing radiation, the researchers blocked an enzyme called telomerase, found in over 90 percent of cancer cells but barely detectable in most normal human cells. In cancer cells, telomerase helps maintain the length of caps on the ends of chromosomes called telomeres. This helps cancer cells replicate indefinitely, grow and spread, Drissi said.

Unraveling DNA stability

Found on chromosomes in both cancerous and normal cells, telomeres are analogous to plastic caps that keep shoestring ends from unraveling. Telomeres help preserve DNA stability in cells by containing genetic miscues. This helps explain why cells with maintained or long telomeres appear to be more resistant to radiation.

In normal cells lacking the telomerase enzyme, telomeres get shorter each time cells divide. They continue doing so until normal cells stop dividing, reaching a condition called senescence. If this first cell-cycle "stop sign" is bypassed, cells continue dividing until telomeres become critically short and reach a second stopping point, when most cells die. In rare instances, cells bypass this second "stop sign" and survive. This survival is often associated with telomerase activation and the onset of cancer.

This was the basis for experiments Drissi and his colleagues conducted to compare the radiation sensitivity and survivability of cells based on telomere length. They also monitored DNA repair responses in the cells by looking for specific biochemical signs that indicate whether the repair systems are working.

The tests involved normal human foreskin cells -- called fibroblasts -- and human cervical carcinoma cells. They exposed the cells to ionizing radiation and analyzed DNA repair responses as telomeres became progressively shorter. In the cervical cancer cells, researchers blocked the telomerase enzyme before radiation treatment to induce progressively shorter telomeres.

Both late-stage noncancerous cells with shorter telomeres, and cancer cells with induced shorter telomeres, were more radiosensitive and died more quickly, according to the study.

Among cancer cells with maintained telomere length, close to 10 percent receiving the maximum dose of ionizing radiation used in the study (8 Gy, or Gray Units) survived the treatment. None of the cancer cells with the shortest telomeres survived that exposure.

Researchers said the cancer cells became more radiosensitive because material inside the chromosomes -- called chromatin -- compacted as telomeres became shorter. Compacted chromatin then disrupted the biochemical signaling of a protein called ATM (ataxiatelangeietasia mutated).

ATM is a master regulator of DNA repair and cell division. It sends signals to activate other biochemical targets (H2AX, SMC1, NBS1 and p53) that help direct DNA repair and preserve genetic stability. In telomere-shortened cancer cells, the compacted chromatin inhibited ATM signaling to all of the chromatin-bound targets tested in the study. This disrupted DNA repair responses and increased radiation sensitivity.

Testing brain cancer cells

The researchers are now testing their findings in cells from hard-to-treat pediatric brain tumors. These tests begin as Drissi's laboratory also leads correlative cancer biology studies of tumor samples from a current clinical trial. The trial is evaluating telomere shortening as a stand-alone therapy for pediatric cancer.

Managed through the National Institutes of Health's Children's Oncology Group (COG), the multi-institutional Phase 1 trial is testing the safety and tumor response capabilities of the drug Imetelstat, which blocks telomerase in cancer cells. Drissi serves on the clinical trial committee along with Maryam Fouladi, MD, MSc, and medical director of Neuro-Oncology at Cincinnati Children's. She leads the medical center's clinical participation in the trial.

Drissi and Fouladi are starting preparatory work to develop, and seek approvals for, a possible clinical trial to test telomere shortening and radiation treatment as a safer, more effective treatment for pediatric brain tumors.

Funding support for the current study in Cancer Prevention Research -- published by the American Society for Cancer Research -- came from the National Institutes of Health, the American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital and Cincinnati Children's Hospital Medical Center. Also collaborating were researchers from Children's National Medical Center in Washington, D.C., and from St. Jude. Funding support for the Drissi lab's correlative studies on the COG clinical trial comes from CancerFree Kids Pediatric Cancer Research Alliance and from Children's Cancer Research Fund.

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The above story is reprinted from materials provided by Cincinnati Children's Hospital Medical Center.

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Journal Reference:

R. Drissi, J. Wu, Y. Hu, C. A. Bockhold, J. S. Dome. Telomere shortening alters the kinetics of the DNA damage response after ionizing radiation in human cells. Cancer Prevention Research, 2011; DOI: 10.1158/1940-6207.CAPR-11-0069

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Less invasive anesthetic methods better for endovascular aneurysm repair

ScienceDaily (Oct. 27, 2011) — Researchers have identified a safer, more cost effective way to provide anesthesia for patients undergoing endovascular repair of an abdominal aortic aneurysm -- a common, often asymptomatic condition that, if not found and treated, can be deadly.

A new study done by investigators at Wake Forest Baptist Medical Center found that using less invasive spinal, epidural and local/monitored anesthesia care (MAC) is better than general anesthesia for elective endovascular repair of infrarenal abdominal aortic aneurysms (EVAR).

Details of the research appear in the November issue of the Journal of Vascular Surgery, the official publication of the Society for Vascular Surgery.

Aortic aneurysms are abnormal bulges, or "ballooning" in the walls of the aorta, the body's largest artery. Roughly the diameter of a garden hose, this artery brings oxygen-rich blood from the heart to the rest of the body. It extends from the heart down through the chest and abdominal region, where it divides into a blood vessel that supplies each leg. Although an aneurysm can develop anywhere along the aorta, most occur in the section running through the abdomen (abdominal aneurysms). An infrarenal abdominal aortic aneurysm is one that occurs in the belly, below the kidney arteries.

Occasionally an aneurysm may occur because of an area of weakness within the artery wall. An aortic aneurysm is serious because it may rupture, causing life-threatening internal bleeding. The risk of an aneurysm rupturing increases as the aneurysm gets larger. Each year, approximately 15,000 Americans die of a ruptured aortic aneurysm, however the condition is usually asymptomatic until the point of rupture. As such, most aortic aneurysms are unexpectedly identified while a patient is having a computed tomography (CT) scan or ultrasound done for another condition. Men over the age of 65 with a history of ever smoking can have an ultrasound done to specifically screen for aneurysms as part of a "Welcome-to-Medicare" visit with their physician. When detected in time, an aortic aneurysm can usually be repaired with surgery.

Infrarenal abdominal aortic aneurysms make up about 95 percent or more of abdominal aortic aneurysms and, while they occur in both sexes, they are most prevalent in men older than 60, affecting about 3 percent of this population, explained study co-author Matthew S. Edwards, B.A., M.S., M.D., a professor of vascular and endovascular surgery and public health sciences at Wake Forest Baptist.

"That's a lot of people," Edwards said. "If aortic aneurysms aren't repaired, they can burst and 80 to 90 percent of people who have a ruptured aortic aneurysm die. It's necessary for those who are suitable candidates for surgery to have their aneurysms repaired."

EVAR has completely revolutionized the care of aneurysms, allowing doctors to do repairs through two small incisions in the groin, Edwards said. It is currently the most common procedure for repairing aortic aneurysms in the United States. Historic trends have led to general anesthesia being the most common mode of anesthesia used for this procedure, but it is sometimes associated with the development of pneumonia, the need for a breathing tube and other pulmonary complications, he explained.

Other anesthetic techniques can also be used, such as local anesthesia, local anesthesia plus sedation (called "monitored" or "MAC"), spinal anesthesia and epidural anesthesia. According to this study, these other methods result in a shortened hospital stay and fewer pulmonary complications.

"In our study, general anesthesia was associated with increased postoperative length of stay (LOS) and increased complications involving the lungs when compared to the other anesthetic methods," Edwards said.

The researchers collected data on 6,009 patients who had elective EVAR performed between 2005 to 2008 at one of 221 North American hospitals. General anesthesia was used in 4,868 of the cases, while 419 patients had spinal anesthesia during their procedure; 331 had epidural anesthesia; and 391 had local/MAC. Emergency cases and patients who had other procedures being done at the same time that required general anesthesia were excluded from the study.

The team then reviewed the data to evaluate rates of mortality, morbidity and length of stay (LOS), or how long the patient remained in the hospital after the procedure.

The researchers found that general anesthesia was associated with an increase in pulmonary complications when compared to spinal and local/MAC anesthesia. Use of general anesthesia also was associated with a 10 percent increase in LOS for general when compared to spinal anesthesia, and a 20 percent increase when compared to general versus local/MAC anesthesia. Trends toward increased pulmonary complications and LOS were not observed for general versus epidural anesthesia. No significant association between anesthesia type and mortality was observed.

"Our study data suggest that increasing the use of less invasive anesthetic techniques, when appropriate, may limit postoperative complications in EVAR patients," Edwards said.

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Journal Reference:

Matthew S. Edwards, Jeanette S. Andrews, Angela F. Edwards, Racheed J. Ghanami, Matthew A. Corriere, Philip P. Goodney, Christopher J. Godshall, Kimberley J. Hansen. Results of endovascular aortic aneurysm repair with general, regional, and local/monitored anesthesia care in the American College of Surgeons National Surgical Quality Improvement Program database. Journal of Vascular Surgery, 2011; 54 (5): 1273 DOI: 10.1016/j.jvs.2011.04.054

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Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

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