Anti-tumor effect of pEgr-interferon-gamma-endostatin gene-radiotherapy in mice bearing Lewis lung carcinoma and its mechanism.
BACKGROUND
Gene-radiotherapy, the combination of gene therapy and radiation therapy, is a new paradigm for cancer treatment. To enhance anti-tumor effect of gene-radiotherapy, in this study we construct a radiation-inducible dual-gene co-expression vector pEgr-interferon (IFN)-gamma-endostatin and studied the anti-tumor effect of pEgr-IFN-gamma-endostatin gene-radiotherapy in mice bearing Lewis lung carcinoma and its mechanism.


METHODS
Gene recombinant technique was used to construct dual-gene co-expression plasmid pEgr-IFN-gamma-endostatin, and single-gene expression plasmid pEgr-IFN-gamma and pEgr-endostatin. The plasmids packed by liposome were injected locally into the tumors of the mice, and the tumors were irradiated with 5 Gy X-ray 36 hours later. The tumor growth rate at different time and mean survival period of the mice were observed. Cytotoxic activity of splenic cytotoxic T-lymphocyte (CTL), natural killer (NK) cell and tumor necrosis factor (TNF)-alpha secretion activity of peritoneal macrophages of the mice in various groups were evaluated 15 days after irradiation. The intratumor micro-vessel density was evaluated by immunohistochemical staining 10 days after irradiation.


RESULTS
The tumor growth rate of the mice in dual-gene-radiotherapy group was significantly lower than those in control group, 5 Gy group and single-gene-radiotherapy group at different time after gene-radiotherapy, and the mean survival period of which was longer. Cytotoxic activity of splenic CTL, NK and TNF-alpha secretion activity of peritoneal macrophages of the mice in dual-gene-radiotherapy group were significantly higher than those in control group, 5 Gy X-ray irradiation group and pEgr-endostatin gene-radiotherapy group 15 days after irradiation. The intratumor micro-vessel density of the mice in dual-gene-radiotherapy group was significantly lower than those in control group, 5 Gy X-ray irradiation group and pEgr-IFN-gammagene-radiotherapy group.


CONCLUSIONS
The anti-tumor effect of dual-gene-radiotherapy was significantly better than that of single-gene-radiotherapy by combining the enhancement of anti-tumor immunologic function induced by IFN-gamma with the anti-angiogenesis function of endostatin.
Yang
Wei
W
Radiobiology Research Unit of Ministry of Health, School of Public Health, Jilin University, Changchun 130021, China.
Li
Xiu-yi
XY
D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004268:DNA-Binding Proteins / Q000235:genetics*; D051766:Early Growth Response Protein 1; D043169:Endostatins / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy; D017874:Immediate-Early Proteins / Q000235:genetics*; D007371:Interferon-gamma / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000628:therapy; D010957:Plasmids; D014157:Transcription Factors / Q000235:genetics*; D014964:X-Ray Therapy
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D043169:Endostatins; D017874:Immediate-Early Proteins; D014157:Transcription Factors; D007371:Interferon-gamma