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Oncolytic Viral Therapy for Cervical and Ovarian Cancer Cells by Sindbis Virus AR339 Strain

Authors' Affiliations: Departments of ¹ Reproductive Medicine, ² Molecular Virology, and ³ Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University; ⁴ Department of Pathology, Social Insurance Funabashi Central Hospital; and ⁵ Division of Gastroenterological Surgery, Chiba Cancer Center Hospital, Chiba, Japan

Requests for reprints: Yuji Shino, Department of Molecular Virology (E2), Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba 260-8670, Japan. Phone: 81-43-226-2044; Fax: 81-43-226-2045; E-mail: yshino{at}faculty.chiba-u.jp.

Purpose: 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.

Experimental Design: In this study, we evaluated the feasibility of the replication-competent SIN AR339 strain as an agent for cervical and ovarian cancer therapy.

Results: 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.

Conclusions: Our study suggested that SIN AR339 strain has a possibility as a novel agent for human cervical and ovarian cancer therapy.

Key Words: Sindbis virus • reovirus • cervical cancer • ovarian cancer • oncolytic virus

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