2-5A antisense telomerase RNA therapy for intracranial malignant gliomas'

Malignant gliomas are the most common intracranial tumors and are considere d incurable, Therefore, exploration of novel therapeutic modalities is esse ntial. Telomerase is a ribonucleoprotein enzyme that is detected in the vas t majority of malignant gliomas but not in normal brain tissues, We, theref ore, hypothesized that telomerase inhibition could be a very promising appr oach for the targeted therapy of malignant gliomas, Thus, 2-5A (5'-phosphor ylated 2'-5'-linked oligoadenylate)-linked antisense against human telomera se RNA component (2-5A-anti-hTER) was investigated for its antitumor effect on an intracranial malignant glioma model. 2-5A is a mediator of one pathw ay of IFN actions by activating RNase L, resulting in RNA degradation. By l inking 2-5A to antisense, RNase L degrades the targeted RNA specifically an d effectively. Prior to the experiments using intracranial tumor models in nude mice, we modified the in vitro and in vivo treatment modality of 2-5A- anti-hTER using a cationic liposome to enhance the effect of 2-5A-anti-hTER . Here we demonstrate that 2-5A-anti-hTER complexed with a cationic liposom e reduced the viability of five malignant glioma cell lines to 20-43% withi n 4 days but did not influence the viability of cultured astrocytes lacking telomerase. Furthermore, treatment of intracranial malignant gliomas in nu de mice with 2-5A-anti-hTER was therapeutically effective compared with the control (P < 0.01). These findings clearly suggest the therapeutic potenti ality of 2-5A-anti-hTER as a novel approach for the treatment of intracrani al malignant gliomas.