A novel triple-regulated oncolytic adenovirus carrying PDCD5 gene exerts potent antitumor efficacy on common human leukemic cell lines.
PDCD5 (programmed cell death 5) accelerates apoptosis of certain tumor cells and the replication-defective Ad-PDCD5 may be a promising agent for enhancing chemosensitivity. In this study, a triple-regulated conditionally replicating adenoviruses (CRAd) carrying PDCD5 gene expression cassette, SG611-PDCD5, was engineered. In SG611-PDCD5, the E1a gene with a deletion of 24 nucleotides within CR2 region is controlled under the human telomerase reverse transcriptase (hTERT) promoter, the E1b gene expression is directed by the hypoxia response element (HRE), whereas the PDCD5 gene is controlled by the cytomegalovirus promoter. The tumor-selective replication of this virus and its antitumor efficacy were characterized in several leukemic cell lines in vitro and in xenograft models of human leukemic cell line in nude mice. It was found by RQ-RT-PCR assay that SG611-PDCD5 expressed PDCD5 efficiently in leukemic cells. In K562 tumor xenograft models, SG611-PDCD5 displayed a tumor killing capacity. At a dose of 1 x 10(9) plaque-forming units, SG611-PDCD5 alone could completely inhibit the tumor growth and more effective than replication-defective Ad-PDCD5. Histopathologic examination revealed that SG611-PDCD5 administration resulted in leukemic cell apoptosis. We concluded that the triple-regulated SG611-PDCD5, as a more potent and safer antitumor therapeutic, could provide a new strategy for leukemia biotherapy.
Xie
Min
M
Peking University People's Hospital and Institute of Hematology, Beijing, China.
Niu
Ji-Hong
JH
Chang
Yan
Y
Qian
Qi-Jun
QJ
Wu
Hong-Ping
HP
Li
Lin-Fang
LF
Zhang
Yao
Y
Li
Jin-Lan
JL
Huang
Xiao-Jun
XJ
Ruan
Guo-Rui
GR
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D015316:Genetic Therapy; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016254:Mutagenesis, Insertional; D009363:Neoplasm Proteins / Q000235:genetics* / Q000627:therapeutic use*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D019076:Transgenes; D023041:Xenograft Model Antitumor Assays
D051017:Apoptosis Regulatory Proteins; D009363:Neoplasm Proteins; C117283:PDCD5 protein, human; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins