Nomura Naohiro, Kasuya Hideki, Watanabe Izuru, Shikano Toshio, Shirota Takashi, Misawa Makoto, Sugimoto Hiroyuki, Kanazumi Naohito, Nomoto Shuji, Takeda Shin, Nakao Akimasa
Department of Surgery II, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Cancer Chemother Pharmacol. 2009 Jan;63(2):321-30. doi: 10.1007/s00280-008-0742-6. Epub 2008 Jun 25.
Oncolytic viral therapy is a newly developed modality for treating tumors. Many clinical trials using oncolytic virus have been performed worldwide, but most of them have used local injection in the tumor. Determination of the effect and safety of intravascular virus injection instead of local injection is necessary for clinical use against multiple liver metastases and systemic metastases.
To evaluate the efficacy and safety of intravascular virus therapy, mice bearing multiple liver metastases were treated by intraportal or intravenous administration of the herpes simplex virus type 1 (HSV-1) mutant, hrR3. Mice treated with hrR3 were killed and organs were harvested for lacZ staining and PCR analysis. Inactivation of oncolytic virus in bloodstream was assessed by neutralization assay in vitro. Infectious activity of hrR3 with vascular endothelial cells was evaluated by replication and cytotoxicity assay.
The survival rate of animals treated by hrR3 was significantly improved compared with the untreated group. lacZ staining and PCR analysis demonstrated detectable virus in the tumor but not in normal tissue or other organs except for the adrenal glands. We also showed that vascular endothelial cells allowed virus replication, while normal hepatocytes did not, and human anti-HSV antibody revealed attenuation of the infectious activity of hrR3.
Intravascular delivery of hrR3 is effective in treating multiple liver metastases, however, several points must be kept in mind at the time of human clinical trials using intravascular virus administration in order to avoid critical side effects.
溶瘤病毒疗法是一种新开发的肿瘤治疗方法。全球已开展了许多使用溶瘤病毒的临床试验，但大多数试验采用肿瘤内局部注射。对于治疗多发性肝转移和全身转移，确定血管内注射病毒而非局部注射的效果和安全性对于临床应用是必要的。
为评估血管内病毒疗法的疗效和安全性，对携带多发性肝转移的小鼠经门静脉或静脉注射1型单纯疱疹病毒（HSV-1）突变体hrR3进行治疗。处死经hrR3治疗的小鼠并采集器官进行β-半乳糖苷酶染色和聚合酶链反应（PCR）分析。通过体外中和试验评估血流中溶瘤病毒的失活情况。通过复制和细胞毒性试验评估hrR3与血管内皮细胞的感染活性。
与未治疗组相比，经hrR3治疗的动物存活率显著提高。β-半乳糖苷酶染色和PCR分析表明，除肾上腺外，肿瘤中可检测到病毒，但正常组织或其他器官中未检测到。我们还表明，血管内皮细胞允许病毒复制，而正常肝细胞则不允许，并且人抗HSV抗体显示hrR3的感染活性减弱。
血管内递送hrR3对治疗多发性肝转移有效，然而，在进行血管内病毒给药的人体临床试验时，必须牢记几点以避免严重的副作用。
