Combination therapy of 2-5A antisense against telomerase RNA and cisplatin for malignant gliomas.
2',5'-Oligoadenylate (2-5A) linked to an antisense oligonucleotide against human telomerase RNA (2-5A-anti-hTR) is a novel therapeutic modality we have recently developed. We designed the oligonucleotide to target telomerase which maintains chromosome integrity in cancer cells. We have already demonstrated the efficacy of this new therapy in malignant glioma cells with telomerase activity. In the present study, we investigated the effect of 2-5A-anti-hTR in combination with cisplatin, an anti-cancer drug commonly used for malignant glioma patients. Six human malignant glioma cell lines with telomerase activity were treated with 0.5 microM 2-5A-anti-hTR and/or cisplatin (0, 0.1, 1, 5, 10, or 20 microg/ml) for three days, and cell viability was measured using the MTT colorimetric assay. The combination therapy showed synergistic effect at 1 microg/ml cisplatin and additive effect at 5 microg/ml cisplatin. TUNEL staining of the treated cells showed significantly increased apoptotic cells after the combination therapy. Furthermore, tumor growth of subcutaneous xenografts of human malignant glioma cells in nude mice was effectively reduced after the combination therapy for seven days. Our study shows that the tumor-killing effects of the combined treatments are, at least in part, due to induction of apoptosis. 2-5A-anti-hTR is a promising therapy not only when used alone, but also in combination with cisplatin.
Kondo
Y
Y
The Center for Surgery Research, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Komata
T
T
Kondo
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016543:Central Nervous System Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002945:Cisplatin / Q000627:therapeutic use*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005910:Glioma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012313:RNA; D016372:RNA, Antisense / Q000627:therapeutic use*; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics* / Q000378:metabolism; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D016372:RNA, Antisense; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase; D002945:Cisplatin