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

BMC Cancer

Tatjana Kozlovska²  Aiva Plotniece¹  Artjoms Spaks³  Dace Skrastina²  Dmitry Zhulenkovs²  Jelena Vasilevska²  Anna Zajakina² 

[1]Latvian Institute of Organic Synthesis, Riga, Latvia

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

[3]P. Stradins Clinical University Hospital, Riga, Latvia

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

Others  :  855512
DOI  :  10.1186/1471-2407-14-460

 received in 2013-12-23, accepted in 2014-06-17,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Zajakina et al.; licensee BioMed Central Ltd.

【 图 表 】

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