2-5A Antisense Telomerase RNA Therapy for Intracranial Malignant Gliomas
2000
Malignant gliomas are the most common intracranial tumors and are
considered incurable. Therefore, exploration of novel therapeutic
modalities is essential. Telomerase is a ribonucleoprotein enzyme that
is detected in the vast majority of malignant gliomas but not in normal
brain tissues. We, therefore, hypothesized that telomerase inhibition
could be a very promising approach for the targeted therapy of
malignant gliomas. Thus, 2-5A (5′-phosphorylated 2′-5′-linked
oligoadenylate)-linked antisense against human telomerase 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 pathway
of IFN actions by activating RNase L, resulting in RNA degradation. By
linking 2-5A to antisense, RNase L degrades the targeted RNA
specifically and 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 liposome reduced the viability of five malignant glioma cell
lines to 20–43% within 4 days but did not influence the viability of
cultured astrocytes lacking telomerase. Furthermore, treatment of
intracranial malignant gliomas in nude mice with 2-5A-anti-hTER was
therapeutically effective compared with the control
( P < 0.01). These findings clearly
suggest the therapeutic potentiality of 2-5A-anti-hTER as a novel
approach for the treatment of intracranial malignant gliomas.
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