Antisense-mediated inhibition of survivin, hTERT and VEGF in bladder cancer cells in vitro and in vivo.
Since cancer cells are characterised by multiple genetic alterations the single inhibition of one tumour- associated gene might not be sufficient as a therapeutic strategy. We examined the effects of a combined inhibition of survivin, human telomerase reverse transcriptase (hTERT) and vascular endothelial growth factor (VEGF) with antisense oligodeoxynucleotides (AS-ODNs) and small interfering RNAs (siRNAs) in EJ28 and 5637 bladder cancer (BCa) cells. Following verification of the uptake of intraperitoneally applied fluorescence-labelled AS-ODNs and siRNAs in subcutaneous BCa xenografts, the target-directed constructs were tested as single agents in SCID mice bearing subcutaneous EJ28. Simultaneous inhibition of two of the selected transcripts significantly enhanced cell viability reduction compared to the controls consisting of a target directed construct and an appropriate control construct without any homology to the human genome. The uptake of both antisense inhibitor types in the subcutaneous BCa was achieved even without a carrier. In vivo studies with 9 consecutive intraperitoneal injections with 20 mg/kg AS-ODNs or 4.6 mg/kg siRNAs revealed the biocompatibility of both antisense inhibitor types and showed anti-tumoural activity of the AS-ODNs used.
Kunze
Doreen
D
Department of Urology, Faculty of Medicine, Technical University of Dresden, 01307 Dresden, Germany. doreen.kunze@uniklinikum-dresden.de
Wuttig
Daniela
D
Kausch
Ingo
I
Blietz
Caroline
C
Blumhoff
Lena
L
Burmeister
Yvonne
Y
Kraemer
Kai
K
Fuessel
Susanne
S
Toma
Marieta
M
Schwenzer
Bernd
B
Meye
Axel
A
Grimm
Marc-Oliver
MO
Hakenberg
Oliver W
OW
Jocham
Dieter
D
Wirth
Manfred P
MP
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism*; D000077022:Survivin; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D014183:Transplantation, Heterologous; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000077022:Survivin; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C509186:TERT protein, human; D019098:Telomerase