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Open Access Research article

High efficiency of alphaviral gene transfer in combination with 5-fluorouracil in a mouse mammary tumor model

Anna Zajakina1*, Jelena Vasilevska1, Dmitry Zhulenkovs1, Dace Skrastina1, Artjoms Spaks2, Aiva Plotniece3 and Tatjana Kozlovska1

Author Affiliations

1 Department of Cell Biology, Biomedical Research and Study Centre, Ratsupites Str., 1, Riga LV-1067, Latvia

2 P. Stradins Clinical University Hospital, Riga, Latvia

3 Latvian Institute of Organic Synthesis, Riga, Latvia

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BMC Cancer 2014, 14:460  doi:10.1186/1471-2407-14-460

Published: 20 June 2014

Abstract

Background

The combination of virotherapy and chemotherapy may enable efficient tumor regression that would be unachievable using either therapy alone. In this study, we investigated the efficiency of transgene delivery and the cytotoxic effects of alphaviral vector in combination with 5-fluorouracil (5-FU) in a mouse mammary tumor model (4 T1).

Methods

Replication-deficient Semliki Forest virus (SFV) vectors carrying genes encoding fluorescent proteins were used to infect 4 T1 cell cultures treated with different doses of 5-FU. The efficiency of infection was monitored via fluorescence microscopy and quantified by fluorometry. The cytotoxicity of the combined treatment with 5-FU and alphaviral vector was measured using an MTT-based cell viability assay. In vivo experiments were performed in a subcutaneous 4 T1 mouse mammary tumor model with different 5-FU doses and an SFV vector encoding firefly luciferase.

Results

Infection of 4 T1 cells with SFV prior to 5-FU treatment did not produce a synergistic anti-proliferative effect. An alternative treatment strategy, in which 5-FU was used prior to virus infection, strongly inhibited SFV expression. Nevertheless, in vivo experiments showed a significant enhancement in SFV-driven transgene (luciferase) expression upon intratumoral and intraperitoneal vector administration in 4 T1 tumor-bearing mice pretreated with 5-FU: here, we observed a positive correlation between 5-FU dose and the level of luciferase expression.

Conclusions

Although 5-FU inhibited SFV-mediated transgene expression in 4 T1 cells in vitro, application of the drug in a mouse model revealed a significant enhancement of intratumoral transgene synthesis compared with 5-FU untreated mice. These results may have implications for efficient transgene delivery and the development of potent cancer treatment strategies using alphaviral vectors and 5-FU.

Keywords:
Semliki Forest virus; Cytotoxic effect; 5-fluorouracil; Combined cancer treatment; 4 T1 tumor