A novel oncolytic adenovirus expressing Escherichia coli cytosine deaminase exhibits potent antitumor effect on human solid tumors.
OBJECTIVE
This study aims to generate a more potent oncolytic adenovirus, Ad.hTERT-E1A/CMV-CD, which combines therapeutic gene and oncolytic effect.


METHODS
A human telomerase reverse transcriptase (hTERT) gene promoter was used to regulate the expression of adenoviral immediate-early gene 1A (E1A) to induce selective replication of recombinant adenovirus in tumor cells. To further enhance antitumor effect, a cytomegalovirus (CMV) promoter-driven Escherichia coli cytosine deaminase (CD) gene expression cassette was further incorporated into E1 region and the antitumor effect of this novel adenovirus was evaluated in vitro and in vivo.


RESULTS
Ad.hTERT-E1A/CMV-CD was capable to selectively replicate and lyse in various human tumor cell lines, including NCIH460, SW1990, and HeLa, while causing no damage to primary fibroblasts. The combined therapy of Ad.hTERT-E1A/CMV-CD with prodrug 5-fluorocytosine (5-FC) elicited a greater killing effect on tumor cells than Ad.hTERT-E1A/CMV-CD alone, and it synergistically suppressed tumor growth in BALB/c nude mice bearing human lung tumor.


CONCLUSIONS
As telomerase is reactivated in a broad spectrum of tumors and prodrug 5-FC is much safe than its metabolized 5-fluorouracil, a chemotherapeutic agent in the treatment of many malignancies, Ad.hTERT-E1A/CMV-CD in combination with 5-FC may be a potential strategy for the treatment of a wide range of solid tumors.
Zhang
Jufeng
J
Experimental Center, Shanghai Jiaotong University, First People's Hospital, People's Republic of China.
Wei
Fang
F
Wang
Huiping
H
Li
Huiming
H
Qiu
Wei
W
Ren
Pengkang
P
Chen
Xiafang
X
Huang
Qian
Q
D000256:Adenoviridae / Q000235:genetics*; D000257:Adenoviridae Infections / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D017500:Adenovirus E1A Proteins / Q000235:genetics; D000818:Animals; D000963:Antimetabolites / Q000627:therapeutic use; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003131:Combined Modality Therapy; D003587:Cytomegalovirus / Q000235:genetics; D043525:Cytosine Deaminase / Q000235:genetics*; D020405:Dermis / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004926:Escherichia coli / Q000201:enzymology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005437:Flucytosine / Q000627:therapeutic use; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D050130:Oncolytic Virotherapy; D011355:Prodrugs / Q000627:therapeutic use; D011401:Promoter Regions, Genetic / Q000235:genetics; D019098:Telomerase / Q000235:genetics; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D017500:Adenovirus E1A Proteins; D000963:Antimetabolites; D011355:Prodrugs; D005437:Flucytosine; C509186:TERT protein, human; D019098:Telomerase; D043525:Cytosine Deaminase