Unno Youichi, Shino Yuji, Kondo Fukuo, Igarashi Natsuhiko, Wang Gang, Shimura Ryuhi, Yamaguchi Taketo, Asano Takehide, Saisho Hiromitsu, Sekiya Souei, Shirasawa Hiroshi
Department of Reproductive Medicine, Graduate School of Medicine, Chiba University, Inohana, Chiba, Japan.
Clin Cancer Res. 2005 Jun 15;11(12):4553-60. doi: 10.1158/1078-0432.CCR-04-2610.
Recently, the application of replication-competent viruses has been studied as anticancer agents. Sindbis virus (SIN) is an RNA virus that belongs to the Alphavirus genus in the Togaviridae virus family. The AR339 strain of SIN has not been reported to induce any serious disease to humans.
In this study, we evaluated the feasibility of the replication-competent SIN AR339 strain as an agent for cervical and ovarian cancer therapy.
SIN infection was able to induce cytopathic effects and apoptosis in two cervical cancer cells (HeLaS3 and C33A) and three ovarian cancer cells (HOC-1, HAC-2, and OMC-3) but not in normal human keratinocytes in vitro. The analysis of cell viability, virus protein synthesis, and viral growth showed the cancer-specific cytotoxicity and virus growth of SIN. In nude mice, i.t. and i.v. inoculation of SIN resulted in significant regression of established cervical tumors implanted at their backs. Histologic studies revealed that systemic treatment with the single injection of SIN induces necrosis within tumors at a remote site. In the metastasis model of ovarian cancer, suppression of ascites formation was observed in nude mice with i.p. SIN treatment. By using an in vivo green fluorescent protein imaging system, we also showed that systemic treatment with SIN targeted tumors specifically.
Our study suggested that SIN AR339 strain has a possibility as a novel agent for human cervical and ovarian cancer therapy.
近来，具有复制能力的病毒作为抗癌剂的应用已得到研究。辛德毕斯病毒（SIN）是一种RNA病毒，属于披膜病毒科甲病毒属。尚未有报道称SIN的AR339株会对人类诱发任何严重疾病。
在本研究中，我们评估了具有复制能力的SIN AR339株作为宫颈癌和卵巢癌治疗药物的可行性。
SIN感染能够在体外诱导两种宫颈癌细胞（HeLaS3和C33A）和三种卵巢癌细胞（HOC-1、HAC-2和OMC-3）出现细胞病变效应和凋亡，但对正常人角质形成细胞无此作用。细胞活力、病毒蛋白合成及病毒生长分析显示了SIN的癌症特异性细胞毒性和病毒生长情况。在裸鼠中，经皮内和静脉接种SIN可使背部植入的已形成的宫颈肿瘤显著消退。组织学研究表明，单次注射SIN进行全身治疗可诱导远处部位肿瘤内出现坏死。在卵巢癌转移模型中，观察到经腹腔注射SIN治疗的裸鼠腹水形成受到抑制。通过使用体内绿色荧光蛋白成像系统，我们还表明经SIN全身治疗可特异性靶向肿瘤。
我们的研究表明，SIN AR339株有可能成为治疗人类宫颈癌和卵巢癌的新型药物。
