A promising cancer gene therapy agent based on the matrix protein of vesicular stomatitis virus.
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 microg 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 (51)Cr 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
Ju-mei
JM
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
Wen
Yan-jun
YJ
Li
Qiu
Q
Wang
Yong-sheng
YS
Wu
Hong-bo
HB
Xu
Jian-rong
JR
Chen
Xian-cheng
XC
Wu
Yang
Y
Fan
Ling-yu
LY
Yang
Han-shuo
HS
Liu
Tao
T
Ding
Zhen-yu
ZY
Du
Xiao-bo
XB
Diao
Peng
P
Li
Jiong
J
Wu
Hong-bing
HB
Kan
Bing
B
Lei
Song
S
Deng
Hong-xin
HX
Mao
Yong-qiu
YQ
Zhao
Xia
X
Wei
Yu-quan
YQ
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000628:therapy; D006224:Cricetinae; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000628:therapy; D051379:Mice; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology; D014721:Vesicular stomatitis Indiana virus; D014763:Viral Matrix Proteins / Q000008:administration & dosage / Q000627:therapeutic use*
D008081:Liposomes; C094460:M protein, Vesicular stomatitis virus; D014763:Viral Matrix Proteins