Oncolytic viral therapy for cervical and ovarian cancer cells by Sindbis virus AR339 strain.
OBJECTIVE
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.


METHODS
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.
Unno
Youichi
Y
Department of Reproductive Medicine, Graduate School of Medicine, Chiba University, Inohana, Chiba, Japan.
Shino
Yuji
Y
Kondo
Fukuo
F
Igarashi
Natsuhiko
N
Wang
Gang
G
Shimura
Ryuhi
R
Yamaguchi
Taketo
T
Asano
Takehide
T
Saisho
Hiromitsu
H
Sekiya
Souei
S
Shirasawa
Hiroshi
H
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D018165:Orthoreovirus / Q000254:growth & development; D010051:Ovarian Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D012845:Sindbis Virus / Q000235:genetics / Q000254:growth & development*; D002583:Uterine Cervical Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D014764:Viral Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
D014764:Viral Proteins; D049452:Green Fluorescent Proteins