AAV-encoded expression of TRAIL in experimental human colorectal cancer leads to tumor regression.
Gene transfer vectors based on the adeno-associated virus (AAV) are used for various experimental and clinical therapeutic approaches. In the present study, we demonstrate the utility of rAAV as a tumoricidal agent in human colorectal cancer. We constructed an rAAV vector that expresses tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L) and used it to transduce human colorectal cancer cells. TRAIL belongs to the TNF superfamily of cytokines that are involved in various immune responses and apoptotic processes. It has been shown to induce cell death specifically in cancer cells. Transduction with AAV.TRAIL gave rise to rapid expression of TRAIL, followed by induction of apoptosis, which could be inhibited by the caspase inhibitor z-VAD.fmk, in several human colon cancer cell lines. The apoptotic mechanism included activation of caspase-3, as well as cytochrome c release from mitochondria. The outgrowth of human colorectal tumors grown in mice was completely blocked by transduction with AAV.TRAIL in vitro, while in vivo transduction significantly inhibited the growth of established tumors. AAV vectors could provide a safe method of gene delivery and offer a novel method of using TRAIL as a therapeutic protein.
University Children's Hospital, Germany.
A
A
Mohr
G
G
Henderson
L
L
Dudus
I
I
Herr
T
T
Kuerschner
K-M
KM
Debatin
H
H
Weiher
K J
KJ
Fisher
R M
RM
Zwacka
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000229:Dependovirus / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D053221:TNF-Related Apoptosis-Inducing Ligand; D014161:Transduction, Genetic / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha