Overexpression of soluble TRAIL induces apoptosis in human lung adenocarcinoma and inhibits growth of tumor xenografts in nude mice.
Recombinant adeno-associated virus 2/5 (rAAV2/5), a hybrid rAAV-2 with AAV-5 capsid, seems to be a very efficient delivery vector for the transduction of the lung adenocarcinoma cell line A549. Infection of the A549 cell line with a rAAV2/5 vector encoding the extracellular domain of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, amino acids 114-281) resulted in secretion of soluble TRAIL (sTRAIL) and induction of apoptosis in these cells. rAAV2/5-sTRAIL mediated delivery and stable expression of sTRAIL resulted in the presence of the trimeric form of sTRAIL in sera of nude mice that were implanted with s.c. or orthotopic A549 tumors. The rAAV2/5-sTRAIL transduction of the tumors resulted in a statistically significant reduction in tumor growth and prolonged survival of the tumor-bearing animals. Primary cell culture, histologic examination of the tumors, and serum analyses showed the absence of detectable TRAIL-induced toxicity in normal tissues including the liver. The successful inhibition of lung cancer growth and the absence of detectable toxicity suggest a putative role for rAAV2/5-sTRAIL(114-281) in the therapy of lung cancer.
Shi
Juan
J
Gene Therapy Laboratory, Genome Research Center, Department of Biochemistry, University of Hong Kong, Pokfulam, Hong Kong.
Zheng
Dexian
D
Liu
Yanxin
Y
Sham
Mai Har
MH
Tam
Paul
P
Farzaneh
Farzin
F
Xu
Ruian
R
D000230:Adenocarcinoma / Q000473:pathology* / Q000628:therapy; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D000229:Dependovirus / Q000235:genetics; D015316:Genetic Therapy; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects; D008175:Lung Neoplasms / Q000473:pathology* / Q000628:therapy; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015996:Survival Rate; D053221:TNF-Related Apoptosis-Inducing Ligand; D014161:Transduction, Genetic; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; 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; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins