Efficient tumor transduction and antitumor efficacy in experimental human osteosarcoma using retroviral replicating vectors

Shuji Kubo,Misato Takagi-Kimura,Noriyuki Kasahara

doi:10.1038/s41417-018-0037-y

Abstract

Retroviral replicating vectors (RRVs) have achieved efficient tumor transduction and enhanced therapeutic benefit in a wide variety of cancer models. Here, we evaluated two different RRVs derived from amphotropic murine leukemia virus (AMLV) and gibbon ape leukemia virus (GALV), which utilize different cellular receptors (PiT-2 and PiT-1, respectively) for viral entry, in human osteosarcoma cells. Quantitative RT-PCR showed that low levels of expression of both receptors were observed in normal and non-malignant cells. However, high PiT-2 (for AMLV) and low PiT-1 (for GALV) expression was observed in most osteosarcoma cell lines. Accordingly, AMLV expressing the green fluorescent protein gene infected and replicated more efficiently than GALV in most osteosarcoma cell lines. Furthermore, RRVs expressing the cytosine deaminase prodrug activator gene showed differential cytotoxicity that correlated with the results of viral spread. AMLV-RRV-mediated prodrug activator gene therapy achieved significant inhibition of subcutaneous MG-63 tumor growth over GALV in nude mice. These data indicate that AMLV vectors predominate over GALV in human osteosarcoma cells. Moreover, our findings support the potential utility of the two RRVs in personalized cancer virotherapy on the basis of receptor expression.

Highlights

Osteosarcoma is the most common primary bone tumor, primarily affecting young children and adolescents [1,2,3,4,5]
We have developed two different Retroviral replicating vectors (RRVs) derived from amphotropic murine leukemia virus (AMLV) and gibbon ape leukemia virus (GALV) [22, 24]
Replicative spread of RRVs in solid tumors are potentially affected by many factors, including cell proliferation rate, antiviral innate immunity, acquired immunity, and cellular receptor expression levels

Summary

Introduction

Osteosarcoma is the most common primary bone tumor, primarily affecting young children and adolescents [1,2,3,4,5]. The use of oncolytic viruses capable of tumor-selective replication has shown considerable promise as a novel treatment strategy [6, 7]. This is based on the observation that tumor cells have impaired antiviral responses making them more sensitive to replicating viruses [8]. Experimental gene therapy for osteosarcoma has utilized only a few oncolytic viruses in the development of replicating viruses, including adenovirus [9,10,11,12,13], Semliki Forest virus [14], and Maraba virus [15]

Methods

Results

Conclusion