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A promising cancer gene therapy agent based on the matrix protein of vesicular stomatitis virus

Ju-mei Zhao^*,,1, Yan-jun Wen^*,1,2, Qiu Li^*,1, Yong-sheng Wang^*,1, Hong-bo Wu^*, Jian-rong Xu, Xian-cheng Chen^*, Yang Wu^*, Ling-yu Fan^*, Han-shuo Yang^*, Tao Liu^*, Zhen-yu Ding^*, Xiao-bo Du^*, Peng Diao^*, Jiong Li^*, Hong-bing Wu^*, Bing Kan^*, Song Lei^*, Hong-xin Deng^*, Yong-qiu Mao^*, Xia Zhao^* and Yu-quan Wei^*

^* State Key Laboratory of Biotherapy, West China Hospital, and

College of Life Science, Sichuan University, Chengdu, Sichuan, China; and

Pharmacological Department of Medical College, Yan’an University, Yan’an, shanxi, China

²Correspondence: State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. E-mail: julio_wy{at}sohu.com

The matrix (M) protein of vesicular stomatitis virus (VSV) plays a key role in inducing cell apoptosis during infection. To investigate whether M protein-mediated apoptosis could be used in cancer therapy, its cDNA was amplified and cloned into eukaryotic expression vector pcDNA3.1(+). The recombinant plasmid or the control empty plasmid pcDNA3.1(+) was mixed with cationic liposome and introduced into various tumor cell lines in vitro, including lung cancer cell LLC, A549, colon cancer cell CT26 and fibrosarcoma cell MethA. Our data showed that the M protein induced remarkable apoptosis of cancer cells in vitro compared with controls. Fifty micrograms of plasmid in a complex with 250 µg cationic liposome was injected intratumorally into mice bearing LLC or MethA tumor model every 3 days for 6 times. It was found that the tumors treated with M protein plasmid grew much more slowly, and the survival of the mice was significantly prolonged compared with the mice treated with the control plasmid. In MethA fibrosarcoma, the tumors treated with M protein plasmid were even completely regressed, and the mice acquired longtime protection against the same tumor cell in rechallenge experiments. Both apoptotic cells and CD8⁺ T cells were widely distributed in M protein plasmid-treated tumor tissue. Activated cytotoxic T lymphocytes (CTLs) were further detected by means of ⁵¹Cr release assay in the spleen of the treated mice. These results showed that M protein of VSV can act as both apoptosis inducer and immune response initiator, which may account for its extraordinary antitumor effect and warrant its further development in cancer gene therapy.—Zhao, J., Wen, Y., Li, Q., Wang, Y., Wu, H., Xu, J., Chen, X., Wu, Y., Fan, L., Yang, H., Liu, T., Ding, Z., Du, X., Diao, P., Li, J., Wu, H., Kan, B., Lei, S., Deng, H., Mao, Y., Zhao, X., Wei, Y. A promising cancer gene therapy agent based on the matrix protein of vesicular stomatitis virus.

Key Words: apoptosis • cellular immune response • plasmid DNA • cationic liposome • cytotoxic T lymphocytes • CTLs