Dec. 9, 1999 (NEW HAVEN) -- Yale Cancer Center researchers have identified two mechanisms to disable the Survivin gene, identified in earlier studies as an inhibitor to apoptosis, the programmed death of cancer cells. The research appears in the December issue of the Journal Nature Cell Biology.
Scientists, led by Dario C. Altieri, M.D., professor of pathology at the Yale University School of Medicine, used two different classes of molecular antagonists to interfere with the function of Survivin and eliminate its protective properties. The first is antisense, a DNA molecule that prevents the transfer of genetic code information from the Survivin gene. The second antagonist is a mutant form of the Survivin itself, but with a function completely unlike that of the original.
According to the in-vitro study using cervical carcinoma cells, both approaches produced one of two different responses. In some cases, the cancer cells died spontaneously. Those that didn't die immediately exhibited a profound defect in cell division, causing them to become unstable and die eventually. "The two independent strategies were comparable in terms of efficacy," said Altieri. "The response to each was of the same frequency and magnitude; the cancer cell is very sensitive to change."
An earlier study led by Altieri identified Survivin as a target in that it acts as a switch for cancer cells, allowing them to stay alive and continue normal cell division. "We now have another piece of the picture of how Survivin functions, and we are hopeful that this new information about potential antagonists can ultimately be used therapeutically. Survivin plays a central role in the cancer cell cycle, and its antagonists may be integrated into first-line treatments. It's one more molecular approach that, when combined with chemotherapy, may prove to increase its effectiveness, Altieri said."
"The distribution of expression of Survivin in human cancers but not in normal adult human cells, and a pattern of expression in cancer cells suggests that interruption of its function may well be one of the prime targets of this decade," said Vincent T. DeVita, Jr., M.D., director of the Yale Cancer Center.
Initial results of preclinical studies at Yale using another strain of mutant Survivin in a melanoma model in mice have shown promise, according to Altieri. And a study using antisense in that same melanoma model is about to get underway.
Other collaborators on the study include Janet Plescia and Annette Rothermel of the Yale University School of Medicine, as well as investigators from the San Raffaele Scientific Institute in Milan, Italy and Isis Pharmaceuticals in Carlsbad, California.
The Yale Cancer Center is one of a select network of comprehensive cancer centers in the country designated by the National Cancer Institute and the only one in Southern New England. Bringing together the resources of Yale-New Haven Hospital and the Yale University School of Medicine, its mission encompasses patient care, research, cancer prevention and control, community outreach and education.
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