Oncolytic Viral Therapy for Prostate Cancer: Efficacy of Reovirus as a Biological Therapeutic
Oncolytic Viral Therapy for Prostate Cancer: Efficacy of Reovirus as a Biological Therapeutic
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DOI：
10.1158/0008-5472.can-09-2408
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发表时间：
2010-03-15
期刊：
影响因子：
11.2
通讯作者：
Morris, Don G.
中科院分区：
文献类型：
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作者：
Thirukkumaran, Chandini M.;Nodwell, Michael J.;Morris, Don G.
呼肠孤病毒是一种非减毒双链 RNA 病毒，它利用异常信号传导途径，对多种癌症组织学产生选择性细胞毒性。此前尚未描述过使用呼肠孤病毒作为前列腺癌的潜在治疗方式，在这项研究中，在临床前模型和六名患者中均发现了体外和体内抗前列腺癌活性的证据。暴露于具有复制能力的呼肠孤病毒的人前列腺癌细胞系 PC-3、LN-CaP 和 DU-145 显示出感染的证据，如病毒蛋白合成、细胞病变效应和病毒子代的释放所示。发现这种溶瘤作用通过细胞凋亡表现出来，在活呼肠孤病毒感染的细胞中观察到 DNA 断裂、Apo 2.7 表达、膜联蛋白 V 结合和聚（ADP-核糖）聚合酶裂解，但在未感染或死病毒处理的细胞中没有观察到。在体内，即使用单次瘤内注射呼肠孤病毒进行治疗，严重联合免疫缺陷/非肥胖糖尿病小鼠异种移植物的后胁部也显示出肿瘤大小的减小。最后，对六名临床器官局限性前列腺癌患者进行病灶内注射呼肠孤病毒，产生了最小的副作用和抗肿瘤活性的证据。前列腺切除术后的组织学分析发现呼肠孤病毒注射区域内有显着的 CD8 T 细胞浸润，并且有证据表明 caspase-3 活性增加。这些发现表明呼肠孤病毒疗法可能为前列腺癌提供一种有前景的新型治疗方法，也意味着病毒免疫靶向肿瘤的可能作用。癌症研究； 70(6)； 2435-44。 (C)2010 AACR。
Reovirus is a nonattenuated double-stranded RNA virus that exploits aberrant signaling pathways allowing selective cytotoxicity against multiple cancer histologies. The use of reovirus as a potential treatment modality for prostate cancer has not previously been described, and in this study evidence of in vitro and in vivo activity against prostate cancer was seen both in preclinical models and in six patients. The human prostate carcinoma cell lines PC-3, LN-CaP, and DU-145 exposed to replication-competent reovirus showed evidence of infection as illustrated by viral protein synthesis, cytopathic effect, and release of viral progeny. This oncolytic effect was found to be manifested through apoptosis, as DNA fragmentation, Apo 2.7 expression, Annexin V binding, and poly(ADP-ribose) polymerase cleavage were observed in live reovirus-infected cells, but not in uninfected or dead virus-treated cells. In vivo, hind flank severe combined immunodeficient/nonobese diabetic murine xenograft showed reduction in tumor size when treated with even a single intratumoral injection of reovirus. Finally, intralesional reovirus injections into a cohort of six patients with clinically organ-confined prostate cancer resulted in minimal side effects and evidence of antitumor activity. Histologic analysis after prostatectomy found a significant CD8 T-cell infiltration within the reovirus-injected areas as well as evidence of increased caspase-3 activity. These findings suggest that reovirus therapy may provide a promising novel treatment for prostate cancer and also imply a possible role for viral immune targeting of tumor. Cancer Res; 70(6); 2435-44. (C)2010 AACR.