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[Cancer Research 61, 3053-3061, April 1, 2001]
© 2001 American Association for Cancer Research

Experimental Therapeutics

Ribozyme Cleavage of Telomerase mRNA Sensitizes Breast Epithelial Cells to Inhibitors of Topoisomerase1

Antje Ludwig, Gabriele Saretzki, Per S. Holm, Frank Tiemann, Mario Lorenz, Thomas Emrich, Calvin B. Harley and Thomas von Zglinicki2

Institute of Pathology, Charité, Humboldt-University, Berlin, Germany [A. L., P. S. H., M. L.]; Hepavec AG, 13122 Berlin, Germany [F. T.]; Roche Diagnostics GmbH, 82372 Penzberg, Germany [T. E.]; Geron Corporation, Menlo Park, California 94025 [C. B. H.]; and Department of Gerontology, University of Newcastle upon Tyne NE4 6BE, United Kingdom [G. S., T. v. Z.]

Telomerase activity is necessary and sufficient for immortality in many cells and hence represents a prime target for antitumor strategies. Here, we show that a hammerhead ribozyme cleaves human telomerase (hTERT) mRNA in vitro. Stable transfection in clones of the human breast tumor line MCF-7 and the immortal breast cell line HBL-100 results in expression of the ribozyme, diminishes the abundance of hTERT mRNA, and inhibits telomerase activity. This led to shortened telomeres, inhibition of net growth, and induction of apoptosis. In HBL-100 mass cultures infected with a ribozyme-expressing adenovirus diminution of hTERT mRNA, attenuation of telomerase activity, inhibition of net growth, and induction of apoptosis was found as well. Attenuation of telomerase activity increased the sensitivity of HBL-100 and MCF-7 clones specifically to inhibitors of topoisomerase. Likewise, expression of exogenous telomerase in originally telomerase-negative human fibroblasts decreased their sensitivity to topoisomerase poisons but not to a number of other cytotoxic drugs. The data validate a ribozyme approach for telomerase inhibition therapy in cancer and suggest that it might be combined advantageously with topoisomerase-directed chemotherapy.




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