Transcriptional targeting of tumors with a novel tumor-specific survivin promoter.
It has been demonstrated that survivin, a novel member of the inhibitor of apoptosis (IAP) protein family, is expressed in human cancers but is undetectable in normal differentiated tissues. We employed a recombinant adenoviral vector (reAdGL3BSurvivin) in which a tumor-specific survivin promoter and a luciferase reporter gene were inserted into the E1-deleted region of adenovirus vector. Luciferase activity was measured in both multiple tumor cell lines and two primary melanoma cells infected with reAdGL3BSurvivin. Human fibroblast and mammary epithelial cell lines were used as negative controls. A reAdGL3CMV, containing the CMV promoter and luciferase gene, was used as a positive control to normalize the luciferase activity generated by the survivin promoter. Our data revealed that the survivin promoter showed high activity in both established tumor cell lines and the primary melanoma cells. In contrast, the in vivo studies indicated that the activities of survivin promoter were extremely low in the major mouse organs. The survivin promoter appears to be a promising tumor-specific promoter exhibiting a "tumor on" and "liver off" profile, and therefore, it may prove to be a good candidate for transcriptional targeting of cancer gene therapy in a wide variety of tumors.
Zhu
Zeng B
ZB
Division of Human Gene Therapy, Department of Medicine, Pathology, and The Gene Therapy Center, University of Alabama at Birmingham, Birmingham AL 35291, USA.
Makhija
Sharmila K
SK
Lu
Baogen
B
Wang
Minghui
M
Kaliberova
Lioudmila
L
Liu
Bin
B
Rivera
Angel A
AA
Nettelbeck
Dirk M
DM
Mahasreshti
Parameshwar J
PJ
Leath
Charles A
CA
Barker
Shannon
S
Yamaoto
Masato
M
Li
Fengzhi
F
Alvarez
Ronald D
RD
Curiel
David T
DT
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D017930:Genes, Reporter / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007527:Isoenzymes / Q000235:genetics; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D009363:Neoplasm Proteins; D009369:Neoplasms / Q000378:metabolism* / Q000628:therapy; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D000077022:Survivin; D014158:Transcription, Genetic / Q000235:genetics
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D000077022:Survivin; D008156:Luciferases; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases