Effective gene-viral therapy of leukemia by a new fiber chimeric oncolytic adenovirus expressing TRAIL: in vitro and in vivo evaluation.
Conditionally replicating adenoviruses (CRAd) have been under extensive investigations as anticancer agents. Previously, we found that ZD55, an adenovirus serotype 5-based CRAd, infected and killed the leukemia cells expressing coxsackie adenovirus receptor (CAR). However, majority of leukemic cells lack CAR expression on their cell surface, resulting in resistance to CRAd infection. In this study, we showed that SG235, a novel fiber chimeric CRAd that has Ad35 tropism, permitted CAR-independent cell entry, and this in turn produced selective cytopathic effects in a variety of human leukemic cells in vitro and in vivo. Moreover, SG235 expressing exogenous tumor necrosis factor-related apoptosis-inducing ligand (SG235-TRAIL) effectively induced apoptosis of leukemic cells via the activation of extrinsic and intrinsic apoptotic pathway and elicited a superior antileukemia activity compared with SG235. In addition, normal hematopoietic progenitors were resistant to the inhibitory activity of SG235 and SG235-TRAIL. Our data suggest that these novel oncolytic agents may serve as useful tools for the treatment of leukemia.
Key Lab of Combined Multi-Organ Transplantation, Institute of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Ministry of Public Health, Hangzhou, People's Republic of China.
Jie
J
Jin
Hui
H
Liu
Chunmei
C
Yang
Gongchu
G
Li
Xinyuan
X
Liu
Qijun
Q
Qian
Wenbin
W
Qian
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D005260:Female; D019254:Genes, bcl-2 / Q000187:drug effects / Q000235:genetics; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007938:Leukemia / Q000473:pathology / Q000628:therapy* / Q000821:virology; D051916:Membrane Cofactor Protein / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D050504:Oncolytic Viruses / Q000235:genetics*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011991:Receptors, Virus / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
C497857:CD46 protein, human; C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D051916:Membrane Cofactor Protein; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011991:Receptors, Virus; D053221:TNF-Related Apoptosis-Inducing Ligand; D020169:Caspases