Adenovirus-mediated GM-CSF gene and cytosine deaminase gene transfer followed by 5-fluorocytosine administration elicit more potent antitumor response in tumor-bearing mice

被引:29
作者
Cao, X
Ju, DW
Tao, Q
Wang, J
Wan, T
Wang, BM
Zhang, W
Hamada, H
机构
[1] Second Mil Med Univ, Dept Immunol, Shanghai 200433, Peoples R China
[2] Japanese Fdn Canc Res, Dept Mol Biotherapy Res, Tokyo, Japan
基金
中国国家自然科学基金;
关键词
cytosine deaminase; suicide gene; gene therapy; adenovirus; granulocyte-macrophage colony-stimulating factor; melanoma;
D O I
10.1038/sj.gt.3300727
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Antitumor effects of combined transfer of suicide and cytokine genes were investigated in this study. Adenovirus harboring E. coli cytosine deaminase gene (AdCD) and adenovirus harboring murine granulocyte-macrophage colony-stimulating factor gene (AdGMCSF) were used simultaneously for in vivo gene transfer in melanoma-bearing mice. Growth inhibition of established tumors and prolongation of survival period were observed more significantly in tumor-bearing mice after transfection with AdGMCSF and AdCD followed by continuous injection of prodrug 5-fluorocytosine (5FC) when compared with mice treated with control adenovirus AdlacZ/5FC, AdCD/5FC or AdGMCSF alone (P < 0.01). After combined therapy the expression of MHC-I (H-2D(b)) and B7-1 molecules on freshly isolated tumor cells increased greatly and more dendritic cells and CD8(+) T cells infiltrated into the tumor mass. The activity of specific cytotoxic T lymphocytes was also found to be induced more significantly after the combined therapy. Further experiments showed that apoptosis of tumor cells and induction of antitumor immune response might be involved in the mechanisms of the tumor cell killing by the combined therapy. Our results demonstrated that combined transfer of the GM-CSF and CD suicide genes, being able to inhibit the growth of melanoma synergistically and induce specific antitumor immune response efficiently thus addressing the drawbacks of suicide gene therapy or cytokine gene therapy which were proved to be not satisfactory when used alone, might be of therapeutic potential for gene therapy of cancer.
引用
收藏
页码:1130 / 1136
页数:7
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