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Enzyme Discovery Could Lead To Cancer Treatment

By Boyce Rensberger
The Washington Post

Scientists have discovered what they say may be the single most critical event that makes all cancer cells effectively immortal and allows them to multiply indefinitely. They say this knowledge could lead fairly quickly to an entirely new form of cancer treatment that could be effective against many or perhaps all forms of the disease.

The crucial event is that highly malignant cancer cells somehow reactivate a long-dormant gene and make an enzyme that reverses a normal process of aging within the cell. As a result, cancer cells can keep on multiplying indefinitely, even as normal cells, whose gene for the enzyme stays dormant, grow old and break down.

Ironically, it is the virtual immortality of the cancer cells that usually dooms the individual in whom they arise. The person's death, of course, kills even "immortal" cancer cells.

The researchers, who are publishing their findings in Tuesday's issue of the Proceedings of the National Academy of Sciences, said Monday they might be just two years away from starting tests of a drug that they hope will block the enzyme in human cancer patients. If the hypothetical treatment worked, cancer cells would, theoretically, lose the benefit of their special enzyme, age quickly, and die.

Although the findings are just emerging from the realm of basic science - not even animals have been tested - leaders of biomedical research hailed them as major advances.

"We're quite optimistic that this is a unique opportunity for inhibiting the growth of cancer cells," said Huber Warner, an official of the National Institute on Aging, one of the National Institutes of Health, which sponsored the research along with the Cancer Research Society of Quebec. A drug that blocked the enzyme should, theoretically, pose no risk to normal cells because it is believed that they do not make the enzyme in the first place. There is, however, one known exception: gonadal cells that make sperm and eggs. They make and use the enzyme because they must be effectively immortal to transmit life to a new generation. A drug that blocked the enzyme might damage these cells and perhaps cause sterility or birth defects.

The new research was led by Calvin B. Harley at McMaster University in Hamilton, Ontario. Harley is temporarily on leave from McMaster and working at Geron Corp., a biotechnology firm in Menlo Park, Calif., that is looking for an enzyme-blocking drug. Collaborating in the research at McMaster were Christopher M. Counter, Hal W. Hirte and Silvia Bacchetti.

What Harley and his Canadian colleagues found was the first direct proof that human cancer cells make an enzyme called telomerase and that normal human cells (except for those of the gonads) do not. Cell and molecular biologists in many labs have been on the trail of telomerase for several years because of tantalizing evidence of its role in cancer and the aging process.

The job of telomerase is to repair a kind of damage that occurs to the tips of chromosomes - the long strands of DNA that carry genes linked end to end - every time a cell divides. This damage appears to be a key part of the aging process.

Prior to cell division, every cell duplicates its chromosomes, so that each of the two resulting cells can have one complete set. But because of the way the DNA-copying machinery works, it cannot duplicate the very tips of chromosomes. 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 about a thousand DNA subunits (or base pairs) that encode nothing

The dummy DNA segments are called telomeres (TEA-low-meers). They also act as caps, stabilizing the ends of the chromosomes. Without telomeres, chromosomes lose their stability and are prone to linking together or even breaking into segments that rejoin in abnormal combinations.

In normal cells of the body (other than those that produce sperm and eggs), bits of telomere DNA are lost each time a cell divides. When the last of the protective sequences is gone, cells become badly deranged and may die.

But cancer cells, Harley has found, are protected against loss of telomeres. Before they have lost the last parts of their telomeres, they somehow reactivate the gene that makes the enzyme, called telomerase, that adds new telomeric DNA every time the cell divides.

"We may be able to directly inhibit telomerase and re-mortalize the cancer cells," Harley said.