The antitumor efficacy of IL-24 mediated by E1A and E1B triple regulated oncolytic adenovirus.
BACKGROUND
IL-24 (interleukin-24) is a promising, multi-functional anti-cancer agent able to selectively induce tumor cell apoptosis while sparing normal cells. Additionally, IL-24 can enhance the immune response to tumors and suppress tumor angiogenesis. In this study, we introduced IL-24 into the oncolytic adenovirus, Ad·sp·E1A((Δ24))·E1B((Δ55))·IL-24. in which E1A was engineered to target Rb (retinoblastoma) deficient or dysfunctional tumors. The survivin promoter (sp), was used to drive expression of IL-24, thereby allowing it to target most tumors. Finally, the 55 KDa gene of E1B was also deleted, thereby preventing replication in normal cells.


RESULTS
Ad·sp·E1A((Δ24))·E1B((Δ55))·IL-24 showed enhanced antitumor effects over the E1, singly regulated oncolytic adenovirus, ONYX-015, in in vitro experiments. Furthermore, Ad·sp·E1A((Δ24))·E1B((Δ55))·IL-24 could effectively inhibit the progression of NCI-H460 lung carcinoma xenografts in nude mice.


METHODS
The antitumor effect of Ad·sp·E1A((Δ24))·E1B((Δ55))·IL-24 was assessed by MTT assay and crystal violet staining in a panel of tumor cells. Cell staining and western blotting for caspase activation were used to assess apoptosis. We assessed the antitumor effects of Ad·sp·E1A((Δ24))·E1B((Δ55))·IL-24 in a xenograft model.


CONCLUSIONS
This is the first study to use an E1A and E1B triple regulated oncolytic adenovirus vector carrying IL-24 to treat large tumors. We attained efficient antitumor effects both in vitro and in vivo, which provides an experimental foundation for clinical cancer therapy.
Xiao
Lian Li
LL
Xinyuan Institute of Medicine and Biotechnology, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China.
Wu
Yu Mei
YM
Qian
Jing
J
Tan
Yuan
Y
Xie
Guo Liang
GL
Zhang
Kang Jian
KJ
Wang
Yi Gang
YG
Jia
Xiao Yuan
XY
Liu
Xin Yuan
XY
D017500:Adenovirus E1A Proteins / Q000235:genetics* / Q000378:metabolism; D017501:Adenovirus E1B Proteins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000099180:Interleukin-24
D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins; D007378:Interleukins; D000099180:Interleukin-24