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New Drug Kills 'Immortal' Cancer Cells in Lab Test

By Boyce Rensberger
The Washington Post

The first test of a possible new approach to treating cancer has caused malignant cells that had been growing for decades in a laboratory dish to lose their "immortality" and to die within weeks.

Many hurdles must be overcome to show whether the process can be turned into a treatment for patients. But the experiments, reported in Friday's issue of the journal Science, provide what the researchers call "proof of principle."

The principle was proposed last year when scientists announced that they had discovered how cancer cells escape a normal process believed to cause most cells in the body to grow old and die. Their research suggested that if cancer cells could be deprived of their escape route, they would die.

This is what has been achieved in the latest experiments.

"We're making progress," said Calvin B. Harley, leader of the scientific group at Geron Corp., a Menlo Park, Calif. biomedical research firm where the studies were done. "We're on track."

Harley cautioned, however, that the particular way in which the cancer cells were deprived of their immortalizing ability in the experiments - dosing them with laboratory-made genes - is not likely to become a useful form of therapy in the near future.

Instead, he said, Geron and Memorial-Sloan Kettering Cancer Center in New York have received a grant from the National Cancer Institute jointly to develop a drug that accomplishes the same goal.

"We have candidates (drugs) that we are testing, but they are not ready for trial in human beings," Harley said.

"I think this is a big deal," said Robert A. Weinberg, a cancer researcher at the Whitehead Institute and Massachusetts Institute of Technology. "This is a significant advance in one of the two most exciting areas of research in cancer therapy." Weinberg, who was not involved with the research, said the other area was angiogenesis, the phenomenon by which cancer cells induce blood vessels to grow into a tumor, nourishing it. Researchers are looking for ways to block that process.

Whether a drug to block the anti-aging mechanism of cancer cells could be both effective and safe is unknown. A key question, according to Carol W. Greider of the Cold Spring Harbor Laboratory on Long Island, N.Y., is whether the process used by cancer cells is also important in normal cells. If so, blocking it with a drug could harm normal parts of the body. Greider said there is evidence that blood-forming cells also use the mechanism.

Greider and colleagues report in the same issue of Science that they are studying the process in mice so they can learn how it functions normally and can test a possible drug treatment on the animals.

At the center of all the research is a natural phenomenon that occurs every time cells prepare to divide - which most cells in the human body do many times during a person's life.

When the cell duplicates its chromosomes so that each of the two daughter cells can have one complete set, parts of the tips of DNA strands are lost, simply because of the way the DNA-copying machinery works. The newly made chromosomes are thus a little shorter than the ones from which they were copied.

This usually causes no problem because the chromosomes of newly fertilized embryos have long stretches of what might be called dummy DNA at the tips. These are sequences of several thousand DNA subunits (or bases) that encode nothing. The dummy DNA is there simply to be lost, a snippet at a time, with every round of cell division.

The dummy DNA is called a telomere. These also act as caps, stabilizing the ends of the chromosomes - much as bands of metal or plastic keep the tips of shoelaces from fraying. Without telomeres, chromosomes lose their stability and may link together or break into segments that rejoin in abnormal combinations. These alterations are detrimental to the cell and, eventually, cause the bodily changes of aging.

In most normal cells of the body, bits of telomere DNA are lost each time a cell divides. When the last of the protective sequences is gone, subsequent cycles of cell division fail to duplicate genes needed by the cell. The daughter cells become badly deranged and may die. The chief exception are cells of the gonads, which must remain able to divide indefinitely from generation to generation without alteration.

They avoid aging by making and using a molecular machine called telomerase. After chromosomes are replicated, this compound guides the manufacture of new telomere sequences, replacing those just lost. Telomerase consists of a protein plus a strand of RNA, a molecule similar to DNA, that serves as a template to guide the process.

Before cancer cells have lost the last of their telomeres, they somehow regain telomerase activity and never again lose the protective DNA end caps. This way, cancer cells can go on dividing endlessly - making new tumors and spreading - without suffering the aging process that dooms normal cells.

Harley and colleagues did their new experiments on a widely used strain of cancer cells, called HeLa, that have been dividing repeatedly in laboratory dishes for decades. To disable the HeLa telomerase, the scientists synthesized a gene that would cause the cancer cells to make a segment of RNA with a genetic sequence exactly opposite to that of the RNA portion of telomerase. When the researchers put the synthetic gene in HeLa cells, the cells began to die after 23 to 26 more division cycles.

Harley said that the same method theoretically should work in cancer patients. But there is no known way to place the synthetic gene in all the cells of a tumor in a body. Instead, he said, the hope is to find or create a conventional molecule that will somehow jam telomerase's ability to function.