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Antisense-mediated hTERT Inhibition Specifically Reduces the Growth of Human Bladder Cancer Cells¹

Department of Urology [K. K., S. F., U. S., M. P. W., A. M.] and Institute of Pathology [M. K.], Technical University Dresden, D-01307, and Institute of Biochemistry, Technical University Dresden, D-01069 [B.S.], Dresden, Germany

Purpose: The expression of human telomerase reverse transcriptase (hTERT) is associated with cellular aging and tumorigenesis. It was found in nearly all cancer types but not in most normal, somatic cells. The aim of this study was to investigate whether hTERT inhibition by antisense oligodeoxynucleotides (AS-ODN) can act as an efficient strategy to specifically impair the growth of bladder cancer (BCa) cells in vitro.

Experimental Design: Twenty-three AS-ODNs were designed complementary to five putative single-stranded target sites using a computer-aided secondary structure prediction of hTERT mRNA. The BCa cell lines were transfected once or several times with AS-ODNs, and the influences on cell growth, hTERT mRNA, and hTERT protein levels, as well as on telomerase activity, were examined.

Results: An immediate and continuous reduction of cell viability (up to a complete cell loss) was achieved by treatment with 5 of 23 tested AS-ODNs in EJ28 cells. Additionally, significant inhibition of proliferation (doubling time, clonogenic survival), as well as an induction of G₁ arrest were observed. The specificity of the growth-inhibitory action of the five efficient AS-ODNs was confirmed by diminished hTERT transcript amount (88%) and reduced hTERT protein content in EJ28 cells. As a consequence, the telomerase activity was inhibited by anti-hTERT treatment 60%. Inhibition of viability was shown for an additional three tested BCa cell lines but not for primary fibroblasts after treatment with the five most effective AS-ODNs supporting an antitumor action of these constructs.

Conclusion: Specific hTERT inhibition causes remarkable short- and long-term effects on the growth of BCa cells and represents a promising new treatment option of solid tumors. We propose that this alternative treatment could be applied in terms of an instillation therapy.

Commentary

Telomerase Therapeutics: Telomeres Recognized as a DNA Damage Signal: Commentary re: K. Kraemer et al., Antisense-mediated hTERT inhibition specifically reduces the growth of human bladder cancer cells. Clin. Cancer Res., 9: 3794–3800, 2003.

Jerry W. Shay
Clin. Cancer Res. 2003 9: 3521-3525. [Full Text] [PDF]

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