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Genetic Screening May Be Tool For Selecting Cancer Treatment, Research Suggests

Date:
July 6, 1998
Source:
Vanderbilt University Medical Center
Summary:
Tumors caused by a specific mutation in the cancer gene BRCA2 appear to be especially vulnerable to radiation and certain chemotherapy drugs, researchers at the Vanderbilt Cancer Center have found. The finding suggests genetic screening might become an effective tool not only for assessing risk of developing cancer but also for tailoring treatment.

Tumors caused by a specific mutation in the cancer gene BRCA2 appear to be especially vulnerable to radiation and certain chemotherapy drugs, researchers at the Vanderbilt Cancer Center have found.

The finding suggests genetic screening might become an effective tool not only for assessing risk of developing cancer but also for tailoring treatment, the scientists report in the July 1 issue of the Journal of the National Cancer Institute.

"This is an exciting strategy because it takes what we know about a genetic defect that causes cancer and uses that knowledge to beat the cancer at its own game," said Dr. Jeffrey T. Holt, professor of Cell Biology and Pathology at Vanderbilt University School of Medicine.

Inherited abnormalities in the BRCA2 gene are responsible for a number of familial cancers, including breast, prostate and ovarian cancer. Mutations in the gene have also been found in about 10 percent of pancreatic cancers.

One of BRCA2's jobs is to help repair breaks in the double strand of DNA inside cells, earlier animal studies demonstrated. Several cancer treatments, including some chemotherapy agents and radiation, work by initiating double-strand breaks in DNA.

Other researchers had suggested that the effect of BRCA2 on double-strand break repair might be exploited for treatment, so Holt and his colleagues -- Derek W. Abbott, Ph.D., and Michael L. Freeman, Ph.D., associate professor of Radiation Oncology -- set out to test that hypothesis.

"Our bodies undergo DNA damage all the time, but most cells can repair breaks in DNA," Holt said. "Usually, when a cell is unable to repair breaks in the DNA, it's a bad thing because it can lead to cancer. In this case, maybe we can use this problem as a strategy for treatment."

The researchers started with a known cancer-causing abnormality in BRCA2 that is common among Ashkenazi Jews. They then found a pancreatic cancer cell line that contained this mutation, and they compared these cells with pancreatic cancer cells that had normal BRCA2 genes.

Using DNA repair tests, the scientists established that cells containing the BRCA2 mutation were strikingly deficient in their ability to repair double-strand DNA breaks.

In-vitro tests then showed that the BRCA2-defective cancer cells were three-to-10-times more sensitive than pancreatic cancer cells with normal BRCA2 genes to three drugs that cause double-strand breaks: mitoxantrone, amsacrine, and etoposide. The two cell lines were equally sensitive to other drugs, paclitaxel and hydroxyurea, which do not cause double-strand DNA breaks, the researchers found.

An increased sensitivity to radiation was also found in animal studies. The researchers induced tumors by injecting pancreatic cancer cells into the thigh muscles of nude mice (specially engineered mice whose bodies do not reject human cells). When the tumors reached a certain size, they were irradiated. The size of the BRCA2-defective tumors decreased 93 percent, while the control tumors did not shrink.

Other tumor-bearing mice were treated with mitoxantrone or etoposide. The tumors grown from BRCA2-defective cells were extremely sensitive to mitoxantrone, with a 96 percent overall reduction in tumor size. Etoposide produced a 45 percent shrinkage in the BRCA2-defective tumors. However, neither drug reduced the size of tumors grown from BRCA2-normal cells.

Holt cautioned against drawing broad conclusions from the studies because the results in mice may not be replicated in patients. Because these studies involved a specific mutation in inherited pancreatic cancer, similar results may not be seen in other cancers caused by other mutations in BRCA2. The work was funded by the National Cancer Institute and the Frances Williams Preston Laboratory of the T.J. Martell Foundation at the Vanderbilt Cancer Center.


Story Source:

The above story is based on materials provided by Vanderbilt University Medical Center. Note: Materials may be edited for content and length.


Cite This Page:

Vanderbilt University Medical Center. "Genetic Screening May Be Tool For Selecting Cancer Treatment, Research Suggests." ScienceDaily. ScienceDaily, 6 July 1998. <www.sciencedaily.com/releases/1998/07/980706080728.htm>.
Vanderbilt University Medical Center. (1998, July 6). Genetic Screening May Be Tool For Selecting Cancer Treatment, Research Suggests. ScienceDaily. Retrieved October 22, 2014 from www.sciencedaily.com/releases/1998/07/980706080728.htm
Vanderbilt University Medical Center. "Genetic Screening May Be Tool For Selecting Cancer Treatment, Research Suggests." ScienceDaily. www.sciencedaily.com/releases/1998/07/980706080728.htm (accessed October 22, 2014).

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