Minicircle-IFNgamma induces antiproliferative and antitumoral effects in human nasopharyngeal carcinoma.
OBJECTIVE
The aims of this work were to investigate the antitumor effect of IFNgamma gene transfer on human nasopharyngeal carcinoma (NPC) and to assess the potential of minicircle vector for antitumor gene therapy.


METHODS
We developed a recombinant minicircle vector carrying the human IFNgamma gene and evaluated the effects of minicircle-mediated IFNgamma gene transfer on NPC cell lines in vitro and on xenografts in vivo.


RESULTS
Relative to p2PhiC31-IFNgamma, minicircle-mediated IFNgamma gene transfer in vitro resulted in 19- to 102-fold greater IFNgamma expression levels in transfected cells (293, NIH 3T3, CNE-1, CNE-2, and C666-1) and inhibited the growth of CNE-1, CNE-2, and C666-1 cells more efficiently, reducing relative growth rates to 7.1 +/- 1.6%, 2.7 +/- 1.0%, and 6.1 +/- 1.6%, respectively. Flow cytometry and caspase-3 activity assays suggested that the antiproliferative effects of IFNgamma gene transfer on NPC cell lines could be attributed to G(0)-G(1) arrest and apoptosis. Minicircle-mediated intratumoral IFNgamma expression in vivo was 11 to 14 times higher than p2PhiC31-IFNgamma in CNE-2- and C666-1-xenografted mice and lasted for 21 days. Compared with p2PhiC31-IFNgamma treatment, minicircle-IFNgamma treatment significantly increased survival and achieved inhibition rates of 77.5% and 83%, respectively.


CONCLUSIONS
Our data indicate that IFNgamma gene transfer exerts antiproliferative effects on NPC cells in vitro and leads to a profound antitumor effect in vivo. Minicircle-IFNgamma is more efficient than corresponding conventional plasmids due to its capability of mediating long-lasting high levels of IFNgamma gene expression. Therefore, minicircle-mediated IFNgamma gene transfer is a promising novel approach in the treatment of NPC.
Wu
Jiangxue
J
State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, PR China.
Xiao
Xia
X
Zhao
Peng
P
Xue
Gang
G
Zhu
Yinghui
Y
Zhu
Xiaofeng
X
Zheng
Limin
L
Zeng
Yixin
Y
Huang
Wenlin
W
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000235:genetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D041681:NIH 3T3 Cells; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy*; D011995:Recombination, Genetic / Q000235:genetics; D013329:Structure-Activity Relationship; D015996:Survival Rate; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D007371:Interferon-gamma