Establishment of novel gene therapy targeting gynecologic tumors

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We established novel methods that inhibit telomerase activity in cancer cells using 2-5Adenylate-linked antisense DNA against human telomerase RNA component (hTR). This antisense DNA effectively blocked telomerase activity in cervical cancer ME180 cells. Growth of ME180 cells in vitro was significantly inhibited by the treatment with 2-5A anti-hTR. Surprisingly, inhibition of cell growth was observed in 24-48 hr after treatment, quite earlier than expected. Telomere length was not shortened in this short period. These findings suggest that blockade of telomerase led to cell growth inhibition via telomere-independent mechanisms. We confirmed that growth inhibition of cells by the treatment with 2-5A anti-hTR was due to induction of apoptosis. The further anaylsis of mechanisms how 2-5A anti-hTR induces apoptosis is on going.We also established novel vector system for cancer gene therapy. We previously cloned promoter of human telomerase reverse transcriptase (hTERT), which is highly specific to cancer cells. We thus used this promoter for cancer-specific gene expression in gene delivery system. Various apoptosis-inducible genes, such as caspase-8 and FADD, were combined with hTERT promoter and used as vectors for cancer gene therapy. Introduction of these vectors effectively induced apoptosis of cancer cells but of surrounding normal tissues.