Combination therapy of malignant glioma cells with 2-5A-antisense telomerase RNA and recombinant adenovirus p53
Combination therapy of malignant glioma cells with 2-5A-antisense telomerase RNA and recombinant adenovirus p53
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DOI：
10.1038/sj.gt.3301327
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发表时间：
2000-12-01
期刊：
影响因子：
5.1
通讯作者：
Kondo, S
中科院分区：
文献类型：
--
作者：
Komata, T;Kondo, Y;Kondo, S
星形细胞起源的恶性胶质瘤通常表现出不同于星形胶质细胞的几个特征，如抑癌基因p53或p16的改变或端粒酶活性的获得。因此，恢复肿瘤抑制基因或抑制端粒酶有望为恶性胶质瘤提供治疗方法。我们最近证明，用2‘，5’-寡腺苷(2-SA-anti-HTR)连接的人端粒酶RNA的19聚体反义寡核苷酸(2-SA-anti-HTR)治疗可以抑制恶性胶质瘤细胞的生长。从治疗的角度出发，研究2-5A-反义hTR联合p53或p16基因修复的抗肿瘤作用具有重要意义。在本研究中，我们评价了2-5A-反义hTR联合携带p53及其相关p21(WAF1/CIP1)或p16(CDKN2)基因的重组腺病毒(Ad5CMV-p53、Ad5CMV-p21或Ad5CMV-p16)在体内外对恶性胶质瘤细胞的抑制作用。5株表达突变型p53基因的恶性胶质瘤细胞株(A172、GB-1、T98G、U251-MG和U373-MG)对2-5A-anti-HTR和Ad5CMV-p53的联合治疗较其他联合治疗更为敏感。联合治疗的相加作用是由于诱导了caspase依赖的细胞凋亡和细胞生长停滞。此外，2-5A-抗HTR治疗联合Ad5CMV-P53对裸鼠皮下U251-MG肿瘤显示出更好的疗效。相反，表达野生型p53基因的U87-MG细胞对Ad5CMV-P53不敏感，但2-5A-anti-HTR处理效果显著。这些结果表明，联合应用2-5A-抗HTR和Ad5-CMV-P53对具有突变型P53的恶性胶质瘤具有最大的治疗潜力。对于显示野生型p53的肿瘤，2-5A-抗HTR治疗可能是有用的。
Malignant gliomas of astrocytic origin have commonly expressed several features such as alterations in the tumor-suppressor gene p53 or p16 or the acquisition of telomerase activity, which are distinctive from astrocytes. Therefore, restoration of the rumor-suppressor gene or telomerase inhibition is expected to provide a cure for malignant gliomas. We have recently demonstrated that the treatment with a 19-mer antisense oligonucleotide against human telomerase RNA linked to a 2',5'-oligoadenylate (2-SA-anti-hTR) inhibited the growth of malignant glioma cells. From a therapeutic point of view, it is very important to investigate the antitumor efficacy of 2-5A-anti-hTR combined with the restoration of p53 or p16 gene. In this study, we evaluated the antitumor effect of 2-5A-anti-hTR in combination with recombinant adenoviruses bearing p53, its associated p21(WAF1/CIP1), Or p16(CDKN2) gene (Ad5CMV-p53, Ad5CMV-p21, or Ad5CMV-p16) against malignant glioma cells in vitro and in vivo. Five malignant glioma cell lines expressing the mutant p53 gene (A172, GB-1, T98G, U251-MG and U373-MG) were more sensitive to the combination of 2-5A-anti-hTR and Ad5CMV-p53 than to other combinations. The additive effect of the combination therapy was due to induction of caspase-dependent apoptosis and cell growth arrest. Furthermore, the 2-5A-anti-hTR treatment when combined with Ad5CMV-p53 showed greater efficacy against subcutaneous U251-MG tumors in nude mice. In contrast, U87-MG cells expressing the wild-type p53 gene were insensitive to Ad5CMV-p53, although the treatment with 2-5A-anti-hTR was significantly effective. These results indicate that combining 2-5A-anti-hTR with Ad5CMV-p53 has the most therapeutic potential for malignant gliomas with mutant p53. For tumors exhibiting wild-type p53, it may be useful to treat with 2-5A-anti-hTR.