Oncolytic adenovirus-mediated transfer of the antisense chk2 selectively inhibits tumor growth in vitro and in vivo.
Screening and identifying molecules target to checkpoint pathways has fostered the development of checkpoint-based anticancer strategies. Among these targets, inhibition of chk2 may induce cell death for tumors whose growth depends on enhanced chk2 activity. However, improvement of the potency and specificity of such therapeutics remains a major challenge. To resolve this problem, we constructed M3, a novel recombinant adenovirus with a 27-bp deletion in E1A CR2 region by which to realize tumor-specific replication, and an 829-bp of antisense chk2 fragment inserted into the E3 coding region. In this design, M3 exploited the native adenovirus E3 promoters to express antisense chk2 cDNA in a viral replication-dependent fashion, and preferentially silenced the chk2 gene in tumor cells. In vitro and in vivo assays confirmed that downregulated chk2 expression induced by M3 infection was tumor-specific and virus replication-dependent. Furthermore, systemic administration of M3 combined with a low dose of cisplatin cured 75% (9/12) of orthotopic hepatic carcinoma mouse models that were otherwise resistant to cisplatin. Our results indicated that the upcoming development in this field would improve the antitumor efficacy and maximize the synergistic effect of oncolytic viruses administered with traditional chemotherapy or radiotherapy.
Chen
G
G
Cancer Biology Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.
Zhou
J
J
Gao
Q
Q
Huang
X
X
Li
K
K
Zhuang
L
L
Huang
M
M
Xu
G
G
Wang
S
S
Lu
Y
Y
Ma
D
D
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002455:Cell Division / Q000235:genetics*; D002460:Cell Line; D064447:Checkpoint Kinase 2; D017931:DNA Primers; D006801:Humans; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
D017931:DNA Primers; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases