Potent anti-tumor effects of a dual specific oncolytic adenovirus expressing apoptin in vitro and in vivo.
BACKGROUND
Oncolytic virotherapy is an attractive drug platform of cancer gene therapy, but efficacy and specificity are important prerequisites for success of such strategies. Previous studies determined that Apoptin is a p53 independent, bcl-2 insensitive apoptotic protein with the ability to specifically induce apoptosis in tumor cells. Here, we generated a conditional replication-competent adenovirus (CRCA), designated Ad-hTERT-E1a-Apoptin, and investigated the effectiveness of the CRCA a gene therapy agent for further clinical trials.


RESULTS
The observation that infection with Ad-hTERT-E1a-Apoptin significantly inhibited growth of the melanoma cells, protecting normal human epidermal melanocytes from growth inhibition confirmed cancer cell selective adenoviral replication, growth inhibition, and apoptosis induction of this therapeutic approach. The in vivo assays performed by using C57BL/6 mice containing established primary or metastatic tumors expanded the in vitro studies. When treated with Ad-hTERT-E1a-Apoptin, the subcutaneous primary tumor volume reduction was not only observed in intratumoral injection group but in systemic delivery mice. In the lung metastasis model, Ad-hTERT-E1a-Apoptin effectively suppressed pulmonary metastatic lesions. Furthermore, treatment of primary and metastatic models with Ad-hTERT-E1a-Apoptin increased mice survival.


CONCLUSIONS
These data further reinforce the previously research showing that an adenovirus expressing Apoptin is more effective and advocate the potential applications of Ad-hTERT-E1a-Apoptin in the treatment of neoplastic diseases in future clinical trials.
Li
Xiao
X
Genetic Engineering Laboratory of PLA, Academy of Military Medical Sciences of PLA, Changchun, China.
Liu
Yan
Y
Wen
Zhongmei
Z
Li
Chang
C
Lu
Huijun
H
Tian
Mingyao
M
Jin
Kuoshi
K
Sun
Lili
L
Gao
Pegn
P
Yang
Encheng
E
Xu
Xiaohong
X
Kan
Shifu
S
Wang
Zhuoyue
Z
Wang
Yuhang
Y
Jin
Ningyi
N
D000256:Adenoviridae / Q000235:genetics* / Q000472:pathogenicity*; D017500:Adenovirus E1A Proteins / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004274:DNA, Recombinant / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D008545:Melanoma / Q000473:pathology; D051379:Mice; D050130:Oncolytic Virotherapy; D009928:Organ Specificity; D040521:Subcutaneous Tissue / Q000473:pathology; D016019:Survival Analysis; D019098:Telomerase / Q000378:metabolism; D019076:Transgenes / Q000235:genetics
D017500:Adenovirus E1A Proteins; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D004274:DNA, Recombinant; C509186:TERT protein, human; D019098:Telomerase