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Telomerase Gene 'Anti-Therapy' Stalls Tumors Growing in Culture

For cancer cells to grow unchecked¿their most notable and lethal trait¿they must divide indefinitely. In normal adult cells, caps at the ends of chromosomes, called telomeres, prevent such activity. Each time a cell replicates, part of the cap is lost and so eventually the cell can no longer divide. But cancer cells get around this natural countdown by reactivating telomerase, an enzyme that rebuilds the telomere tips after each successive split. Now Elizabeth Blackburn, a co-discoverer of telomerase, and her colleagues at the University of California at San Francisco say they have found a way to disrupt the enzyme in tumor cells. And in a series of experiments, described today in the Proceedings of the National Academy of Sciences, their method slowed or halted the growth of cancer cells in culture and in mice.

The researchers inserted a very tiny mutation in a gene that encodes telomerase RNA¿a short sequence of RNA that acts as a template for building the DNA telomere tips. The change did not affect all of the telomeres in test cells but rather "uncapped" a few per cell, Blackburn says. Still, it was enough to prompt a DNA damage response in most of the cells, causing them to stop dividing or actually commit suicide. "We were quite surprised at how strong the effect was," Blackburn says. "Cancer cells are tough. They usually ignore the signals that tell them to commit suicide. But by spiking the telomerase enzyme with just a little bad telomerase, we saw a powerful effect."

The researchers now plan to explore the therapeutic potential of the approach further. They will first test the method on human cancer cells newly derived from patients, which may behave differently from the cultured cells in the experiments reported here. And they will investigate other ways to alter the gene (gene anti-therapies), as well as small molecules that might warp telomerase in the same way. Because normal cells do not produce telomerase, any remedy that affects it should not damage healthy tissues¿a major drawback of many current cancer treatments. "Success will depend on the details and identifying a method of delivery," Blackburn says, "but it is one of many reasonable targets out there."

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