Effective gene-viral therapy for telomerase-positive cancers by selective replicative-competent adenovirus combining with endostatin gene.
Gene-viral therapy, which uses replication-selective transgene-expressing viruses to manage tumors, can exploit the virtues of gene therapy and virotherapy and overcome the limitations of conventional gene therapy. Using a human telomerase reverse transcriptase-targeted replicative adenovirus as an antiangiogenic gene transfer vector to target new angiogenesis and making use of its unrestrained proliferation are completely new concepts in tumor management. CNHK300-mE is a selective replication transgene-expressing adenovirus constructed to carry mouse endostatin gene therapeutically. Infection with CNHK300-mE was associated with selective replication of the adenovirus and production of mouse endostatin in telomerase-positive cancer cells. Endostatin secreted from a human gastric cell line, SGC-7901, infected with CNHK300-mE was significantly higher than that infected with nonreplicative adenovirus Ad-mE in vitro (800 +/- 94.7 ng/ml versus 132.9 +/- 9.9 ng/ml) and in vivo (610 +/- 42 ng/ml versus 126 +/- 13 ng/ml). Embryonic chorioallantoic membrane assay showed that the mouse endostatin secreted by CNHK300-mE inhibited angiogenesis efficiently and also induced distortion of pre-existing vasculature. CNHK300-mE exhibited a superior suppression of xenografts in nude mice compared with CNHK300 and Ad-mE. In summary, we provided a more efficient gene-viral therapy strategy by combining oncolysis with antiangiogenesis.
Zhang
Qi
Q
Laboratory of Viral and Gene Therapy, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
Nie
Mingming
M
Sham
Jonathan
J
Su
Changqing
C
Xue
Huibin
H
Chua
Daniel
D
Wang
Weiguo
W
Cui
Zhenfu
Z
Liu
Yongjing
Y
Liu
Chen
C
Jiang
Minghong
M
Fang
Guoen
G
Liu
Xinyuan
X
Wu
Mengchao
M
Qian
Qijun
Q
D000256:Adenoviridae / Q000235:genetics; D000482:Allantois; D000818:Animals; D002645:Chickens; D043169:Endostatins / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000473:pathology / Q000502:physiology; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000473:pathology* / Q000821:virology*; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019098:Telomerase / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014779:Virus Replication
D043169:Endostatins; D019098:Telomerase