Treatment of bladder cancer cells in vitro and in vivo with 2-5A antisensetelomerase RNA

Bladder cancer is the most common malignant tumor of the urinary tract. Nov el treatment approaches are essential because of the failure of current Tre atment options to cure a high percentage of patients. Telomerase, a ribonuc leoprotein, is detected in almost all bladder cancer, but not in normal bla dder tissues. Therefore. telomerase is expected to be a very promising cand idate for targeted therapy of bladder cancer. In this study, We synthesized a 19-mer antisense oligonucleotide against the RNA component of human telo merase (hTR) linked to a 2-5A molecule (2-5A-anti-hTR) and investigated its antitumor effect against bladder cancer cells. The 2-5A antisense strategy relies on the recruitment and activation of RNase L at the site of targete d RNA sequence. Here we demonstrate that treatment with 2-5A-anti-hTR reduc ed the viability of seven bladder cancer cell lines (UM-UC-2, UM-UC-3, UM-U C-6, UM-UC-9, UM-UC-14,, RT4 and T24) expressing telomerase activity to 21- 55% within 4 days. The cytotoxicity was mainly due to induction of caspase- dependent apoptosis. In contrast, normal fibroblast W138 cells lacking telo merase activity were resistant to the treatment. Furthermore, treatment of subcutaneous UM-UC-2 tumors in nude mice with 2-5A-anti-hTR significantly s uppressed the tumor growth through induction of apoptosis (P < 0.001). Thes e findings may offer a strong support to the feasibility of the 2-5A-anti-h TR treatment for human bladder cancer.