Abstract
BackgroundVA7 is a neurotropic alphavirus vector based on an attenuated strain of Semliki Forest virus. We have previously shown that VA7 exhibits oncolytic activity against human melanoma xenografts in immunodeficient mice. The purpose of this study was to determine if intravenously administered VA7 would be effective against human glioma.Methodology/Principal Findings In vitro, U87, U251, and A172 human glioma cells were infected and killed by VA7-EGFP. In vivo, antiglioma activity of VA7 was tested in Balb/c nude mice using U87 cells stably expressing firefly luciferase in subcutaneous and orthotopic tumor models. Intravenously administered VA7-EGFP completely eradicated 100% of small and 50% of large subcutaneous U87Fluc tumors. A single intravenous injection of either VA7-EGFP or VA7 expressing Renilla luciferase (VA7-Rluc) into mice bearing orthotopic U87Fluc tumors caused a complete quenching of intracranial firefly bioluminescence and long-term survival in total 16 of 17 animals. In tumor-bearing mice injected with VA7-Rluc, transient intracranial and peripheral Renilla bioluminescence was observed. Virus was well tolerated and no damage to heart, liver, spleen, or brain was observed upon pathological assessment at three and ninety days post injection, despite detectable virus titers in these organs during the earlier time point.ConclusionVA7 vector is apathogenic and can enter and destroy brain tumors in nude mice when administered systemically. This study warrants further elucidation of the mechanism of tumor destruction and attenuation of the VA7 virus.
Highlights
During the past decades malignant gliomas have presented with an insurmountable obstacle in cancer treatment
While recent results of a multi-center phase III clinical trial combining radiotherapy (RT) with the DNA-alkylating agent temozolomide (TMZ) have marked a true paradigm shift in treatment of glioblastoma multiforme (GBM) [1], the most common type of malignant glioma, patients rarely live beyond two years after diagnosis and there are no cures
We have described the oncolytic potential of VA7EGFP against human melanoma xenografts in severe combined immunodeficient (SCID) mice [32]
Summary
During the past decades malignant gliomas have presented with an insurmountable obstacle in cancer treatment. Other reasons for treatment failure are the vast genotypic and phenotypic heterogeneity of malignant gliomas, limiting the effectiveness of any single therapeutic on a population-wide scale, and the presence of tumorigenic cells capable of both resisting conventional therapies as well as escaping immune surveillance [4]. Tumor-initiating cells (TICs) were indentified in malignant gliomas [5]. These cells were later shown to be resistant to ionizing radiation which could well explain why radiation therapy fails to kill malignant gliomas [6]. The purpose of this study was to determine if intravenously administered VA7 would be effective against human glioma
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
