[Inhibitory effect of adenovirus-mediated endostatin gene transfer on transplanted lung carcinoma in mice].
OBJECTIVE
To investigate the effect of adenovirus-mediated endostatin gene transfer on transplanted lung cancer in mice and its mechanism of action.


METHODS
Transplant tumor model was induced by subcutaneous inoculation of 2 x 10(6) Lewis lung cancer (LLC) cells into the back of C57BL/6 mice. The mice were treated by intratumoral injection of 2 x 10(9) pfu Ad-mEndostatin. The expression of endostatin in situ and its maintaining time were detected by immunohistochemistry and Western Blot, respectively. The endostatin level in serum was determined by ELISA . The inhibition of tumor growth and changes of survival were recorded and the microvessel density (MVD) was determined by histochemical stainingwith CD31 and CD105 antibodies. The tumor apoptosis was observed by electron microscopy.


RESULTS
In comparison with controls, intratumoral injection of Ad-mEndostatin significantly inhibited the tumor growth and metastasis, and prolonged the survival rate of mice (P < 0.05). Strong positive expression of mEndostatin was seen in the tumor tissue after injection of Ad-mEndostatin, immunhistochemically ostained by mouse endostatin monoclonal antibody, while the control groups showed only very low expression or absence. Serum endostatin concentration was 1540 +/- 560 ng/ml at the second week of administration, the expression of endostatin diminished a month later. The microvessel density (MVD)) decreased from 42.4 +/- 4.8 to 10.5 +/- 3.2 per x 200 magnificetion microscopic field by CD10 staining and from 68.5 +/- 4.5 to 37.5 +/- 4.6 by CD31 staining, respectively (P < 0.05). More apoptotic tumor cells were seen under the transmission electron microscope.


CONCLUSIONS
Endostatin gene therapy mediated by adenoviral vector efficiently induces expression of endostatin in vivo, and inhibits the growth and metastasis of tumor. It is concluded that its action is targeted to tumor neovasculature and the mechanism is inhibition of tumor angiogenesis.
Sui
Gang
G
Department of Thoracic Surgery, Jinan General Hospital of PLA, Jinan 250031, China.
Xu
Zhi-Fei
ZF
Sun
Yao-Chang
YC
Liu
Yong-Jing
YJ
Wu
Li-Hui
LH
Qin
Xiong
X
D000256:Adenoviridae / Q000235:genetics*; D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D043169:Endostatins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D015316:Genetic Therapy; D005822:Genetic Vectors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000473:pathology; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology; D011897:Random Allocation; D014162:Transfection; D047368:Tumor Burden
D020533:Angiogenesis Inhibitors; D043169:Endostatins