Ribozyme-mediated telomerase inhibition induces immediate cell loss but not telomere shortening in ovarian cancer cells

Telomerase is a promising target for human cancer gene therapy. Its inhibit ion allows telomere shortening to occur in cancer cells, which in turn is t hought to trigger delayed senescence and/or apoptosis. We tested whether te lomerase inhibition might have additional, immediate effects on tumor cell growth. Ovarian cancer cell lines with widely differing telomere lengths we re efficiently transduced with an adenovirus expressing a ribozyme directed against the T motif of the catalytic subunit of human telomerase, hTERT. T hree days after transduction, telomerase activity was significantly reduced and massive cell loss was induced in mass cultures from all four ovarian c ancer cell lines tested, whereas transduction of telomerase-negative human fibroblasts did not attenuate their growth, The kinetics of induction of ce ll death in cancer cells was not significantly dependent on telomere length , and telomeres did not shorten measurably before the onset of apoptosis. T he data suggest the existence of a "fast-track" mechanism by which diminuti on of telomerase can interfere with cancer cell growth and induce cell deat h, presumably by apoptosis. This phenomenon might be a consequence of the t elomere capping function provided by telomerase in tumor cells. Uncapping o f telomeres by ribozyme-mediated inhibition of telomerase bears therapeutic potential for ovarian cancer.