Navigation Links
Cancer cells' DNA repair disrupted to increase radiation sensitivity

CINCINNATI 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 repair

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 cancers.

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.


Contact: Nick Miller
Cincinnati Children's Hospital Medical Center

Related medicine news :

1. First whole-genome sequencing clinical trials for triple-negative breast cancer presented
2. Genetic sequencing could help match patients with biomarker-driven cancer trials, treatments
3. Lobular Breast Cancer Linked to Paternal Cancer History
4. Womens High Blood Sugar Linked to Colorectal Cancer: Study
5. High blood sugar levels in older women linked to colorectal cancer
6. Men More Likely to Skip Cancer Screenings: Study
7. Gene acts as a brake on breast cancer progression
8. NTU-led research probes potential link between cancer and a common chemical in consumer products
9. New study shows biopsy of recurrent breast cancer can alter treatment
10. Risk of second cancer in cancer survivors mainly confined to the same cancer type as the first
11. Second Cancer Often Same Type as the First, Study Finds
Post Your Comments:
(Date:11/27/2015)... CA (PRWEB) , ... November 27, 2015 , ... According ... at the recent 2015 American Dental Association meeting in Washington D.C. revolved around the ... protect a patient’s overall health. The talk stressed the link between periodontal disease (more ...
(Date:11/27/2015)... ... 2015 , ... A team of Swiss doctors has released a report on ... just posted the findings on the website. Click here to read the details ... mesothelioma patients who were treated with chemotherapy followed by EPP surgery. Among the 106 ...
(Date:11/27/2015)... ... November 27, 2015 , ... ... edition of USA Today in Atlanta, Dallas, New York, Minneapolis, South Florida, with ... digital component is distributed nationally, through a vast social media strategy and across ...
(Date:11/27/2015)... ... 2015 , ... Intellitec Solutions announced today that they have ... as Microsoft’s official group for end users of Dynamics SL ERP software, the ... experts and representatives. Intellitec Solutions’ membership status demonstrates their ongoing commitment to the ...
(Date:11/27/2015)... , ... November 27, 2015 , ... CBD College ... of Allied Health Education Programs (CAAHEP) awarded accreditation to its Diagnostic Medical Sonography program. ... accredited colleges, as only one of twelve colleges and universities in the state of ...
Breaking Medicine News(10 mins):
(Date:11/26/2015)... 2015 ) ... "2016 Future Horizons and Growth Strategies in ... Supplier Shares, Country Segment Forecasts, Competitive Intelligence, ... --> ) has announced ... Horizons and Growth Strategies in the French ...
(Date:11/26/2015)... , November 26, 2015 ... Juntendo universitetssjukhus ser potential att använda SyMRI ... (MR-bilder) för patienter med multipel skleros ... forskningsavtal med SyntheticMR AB för att kunna ... på sjukhuset. Med SyMRI kan man generera ...
(Date:11/26/2015)... November 26, 2015 ... adds "Global Repaglinide Industry ... Report on China Repaglinide Market, 2010-2019" ... data and information to its online ... . --> ...
Breaking Medicine Technology: