2-5A antisense telomerase RNA therapy for intracranial malignant gliomas.
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.
Mukai
S
S
Center for Surgery Research, The Cleveland Clinic Foundation, Ohio 44195, USA.
Kondo
Y
Y
Koga
S
S
Komata
T
T
Barna
B P
BP
Kondo
S
S
D000227:Adenine Nucleotides / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D002411:Cation Exchange Resins / Q000494:pharmacology; D002412:Cations; D005260:Female; D005910:Glioma / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D006801:Humans; D008055:Lipids / Q000494:pharmacology; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009843:Oligoribonucleotides / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D020320:Oligoribonucleotides, Antisense / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology*; D012334:RNA, Neoplasm / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics; D014407:Tumor Cells, Cultured
D000227:Adenine Nucleotides; D002411:Cation Exchange Resins; D002412:Cations; D008055:Lipids; C086724:Lipofectamine; D008081:Liposomes; D009843:Oligoribonucleotides; D020320:Oligoribonucleotides, Antisense; D012334:RNA, Neoplasm; C023505:2',5'-oligoadenylate; D019098:Telomerase