Telomerase activity has been found in most types of human tumors, but not in adjacent normal cells. This correlation has led to the hypothesis that reactivation of telomerase is necessary for the sustained proliferation that characterizes cancer, and that telomerase is a novel target for chemotherapy. The validity of this hypothesis has been vigorously debated, and effective inhibitors of telomerase are needed to understand how blocking telomerase activity will affect cancer cell phenotypes and proliferation. To discover the potential for telomerase as a target for chemotherapy Dr. Corey is developing oligonucleotides and oligonucleotide mimics as highly selective and potent inhibitors. These oligomers are well suited to achieving unambiguous insights into the consequences of telomerase inhibition because they take advantage of the potential for stringently selective recognition inherent in Watson-Crick base-pairing. An oligomer complementary to a target sequence should exert a sequence-specific physiologic effect, whereas the mismatch containing oligomer should not. They now propose to continue to develop synthetic telomerase inhibitors, characterize the effects of telomerase inhibition on the proliferation of varied lines of cultured cells, and perform preclinical studies in mouse models of human cancer. This research will be integrated into a cycle of experiments in which the observed effects of inhibitors in cell culture and animals will rapidly lead to revised inhibitor designs and renewed testing for efficacy. These studies will characterize the in vivo effects of inhibitors of telomerase, permit investigation of the side effects of antitelomerase therapy, and provide insights that will be generally applicable to the development of all classes of telomerase inhibitors.
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