Aging is definitely hazardous to one's health. And the smoking gunthat makes senescence so deadly seemingly turns out to be an enzymethat pops up in the chromosomes of cells slated to turn cancerous.That molecular verdict was spelled out yesterday in a press conferencesponsored by the National Institute on Aging (NIA) of Bethesda, Md.Geron Corp.'s director of cell biology, Calvin Harley, described therole of telomerase, the "immortalizing enzyme." It makes precancerouscells immortal _ that is, malignant.NIA staged the press briefing, at the National Press Club, to highlightHarley's paper in today's (April 12) issue of the Proceedings of theNational Academy of Sciences (PNAS). His paper, "Telomeraseactivity in human ovarian carcinoma," reported these two "firsts,"according to Geron's vice president of finance and administration, JerylHilleman:y "It's the first published finding that telomerase is present in cancercells specifically, but not in normal cells. Hence its potential as "asingle, specific target for antitumor drugs.y "It shows that the telomere lengths of the cancer cells is significantlyshorter than normal cells."Updating his PNAS paper, Harley told the press briefing that recentwork at Menlo Park, Calif.-based Geron has "detected telomerase sofar in six of the 10 most prevalent later-stage, highly malignantcancers."Besides implications for cancer therapy, he said, these findings extendto "a whole variety of other age-related diseases, such asatherosclerosis, osteoarthritis and a decrease of immune response in theelderly."At Geron, Harley directs the telomerase inhibition program, a majorhigh-through-put effort to screen enzyme-inhibiting compounds fordrugs that could stop telomerase in its DNA tracks, and thus executethose cells turned cancerous."We're searching for small-molecule inhibitors of the enzyme itself,Harley told BioWorld Today, rather than looking at gene therapystrategies." Because telomerase is a DNA polymerase, this huntthrough numerous chemical libraries is testing known inhibitors ofvarious DNA-modifying enzymes, including polymerases and reversetranscriptases.In past research, Harley, then at McMaster University in Hamilton,Ontario, has shown that the cellular aging process seems to becontrolled by a "molecular clock," consisting of repeating DNAsegments capping the ends of chromosomes. These telomeres consist ofmultiple, tandem repeat DNA sequences _ all TTAGGG."You start off as a fertilized egg," Hilleman told BioWorld Today,"with some 15 kilobase pairs (kbp) of the six-base-pair sequence,totaling about 2,000 repeats at each end of every chromosome." Eachcell division during gestation whittles 50 to 100 bp off that chain ofrepeats. At birth, a neonate's chromosomes enter the world with 10kbp.After perhaps 50 divisions, a cell reaches the Hayflick Limit at about 5kbp, stops dividing and becomes senescent. In cells destined formalignancy, telomerase kicks in before this ultimate aging stage to stopthe repeat shortening. This renders the cell immortal, hence malignant.In their PNAS study, Harley and his collaborator at McMaster, SylviaBacchetti, compared malignant and non-malignant cells frommetastatic ovarian-cancer patients, and found telomerase only in thecancerous ones.Because the immortalizing enzyme does not operate in healthy cells,Harley pointed out, "drugs that specifically inhibit telomerase activitywould have minor or non-existent side effects."He said that "if we're lucky, we hope to have a candidate in the clinicwithin two years, and animal tests very quickly."Huber Warner, of NIA's Biology of Aging Program, said, "To me theexcitement here is finding a way to develop a cancer treatment thatavoids the dreadful side effects of many of the drugs we now have," Headded, "In any drug therapy, targeting is an important issue. Since thisenzyme activity is seen only in cancerous and reproductive cells,noncancerous cells in the body, such as those normally found in theliver or kidney, would not be affected by a possible therapy that couldinhibit ovarian cancer growth."NIA has given financial support to Harley's work at McMaster and atGeron. Summing up, Harley observed: "Biology is very complex, and Idon't think this is going to be the magic bullet that will work in 100percent of all cancers. But I am optimistic that this new approach willbe effective in many malignancies."

-- David N. Leff Science Editor

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