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Study shows retinoids kill childhood brain tumor cells
Researchers have found that derivatives of vitamin A may be effective in treating medulloblastoma, the most common form of childhood brain cancer.
Because the compounds, called retinoids, have already been approved by the FDA for treatment of another childhood cancer, neuroblastoma, researchers expect that the drugs will enter clinical trials in pediatric medulloblastoma patients with minimal delay.
The study led by Drs. Andrew Hallahan and James Olson of Fred Hutchinson Cancer Research Center showed that retinoids killed cancer cells from medulloblastoma tumors that had been surgically removed from patients as well as tumors that had been grafted onto mice. The study appears in the Aug. 3 issue of Nature Medicine.
According to Hallahan, retinoids could prove to be even more effective at treating medulloblastoma than neuroblastoma. Through genome analysis, the scientists also identified a protein in medulloblastoma cells that is triggered by retinoids to initiate cell death, a finding that is likely to lead to the development of additional therapies for the disease.
"These compounds work against neuroblastoma and other cancers because they trigger cells to differentiate (form specialized cells) and stop dividing," Hallahan said in a prepared statement. "But we observed that when the compounds are applied to medulloblastoma tumors, a large percentage of cancer cells actually die."
Medulloblastomas arise from primitive cells in the back of the brain, or cerebellum, a region important for motor control and spatial orientation. The disease primarily strikes children under the age of 7. Standard therapy, which includes surgical removal of the tumor followed by radiation and a year of chemotherapy, offers about a 70 percent chance of survival for children over age 3 who do not have recurrent cancer.
High-risk children, who include those under age 3 or who have recurrent disease, have a much lower chance of survival with standard therapy. For that reason-and because of the toxic side effects of radiation and chemotherapy in young children-scientists are urgently seeking new treatments.
Retinoids are molecules naturally produced by the human body, where they play a critical role in normal development by triggering primitive cells to become specialized cells characteristic of a particular tissue, such as nerve cells in the brain. Scientists also have created synthetic retinoids, which have proved to be effective against some tumors because they drive cancer cells from their relatively primitive, undifferentiated state into specialized cells that cease to divide.
Hallahan and colleagues examined the effect of three retinoids on medulloblastoma tumor specimens obtained from surgeries in patients treated at Children´s Hospital and Regional Medical Center in Seattle.
"This was a critical step because it was uncertain whether the available medulloblastoma cell lines (cells previously extracted from tumors and grown indefinitely in the laboratory) would accurately reflect the disease," said Olson.
The experiment led to a surprising result. While the retinoids did push about 5 to 10 percent of the medulloblastoma cells to specialize, a large number of tumor cells died.
Using DNA microarrays, which permit the analysis of thousands of genes simultaneously, they identified a protein called BMP-2 (bone morphogenetic protein-2), which produces a protein that triggered a series of genes that activated programmed cell death.
Olson said BMP-2 or other proteins "downstream" in the retinoid-induced cell-death cascade could be potential targets for new anticancer drugs.
Until then, a proposed clinical trial for high-risk pediatric medulloblastoma patients to compare standard therapy plus retinoids to standard therapy alone is now under review by the Children´s Oncology Group, a National Cancer Institute-supported clinical trials cooperative focused exclusively on childhood and adolescent cancers Olson, who will serve as principal investigator of the study, hopes to begin the trial at 235 hospitals sometime within the next year.
Source: cancerfacts
Tuesday, August 05, 2003
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