Effective gene-viral therapy of leukemia by a new fiber chimeric oncolytic adenovirus expressing TRAIL: in vitro and in vivo evaluation

Abstract

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. [Mol Cancer Ther 2009;8(5):1387-97]

Anticancer Gene Transfer for Cancer Gene Therapy

“…TRAIL oncolytic gene therapy utilized the chimeric Adenovirus AD5/35 which is able to transduce cancer cells without the use of a receptor, replicate in cancer cells and allow TRAIL expression which lead to apoptosis induction (Chen et al, 2009). Efficacy of this vector was shown in leukemia, gastric cancer and pancreatic cancer in vivo (Zhang et al, 2009b, Jin et al, 2009. TRAIL has been extensively analyzed in a previous chapter of this book since it is one of the "anticancer genes" which are able to promote tumor-specific apoptosis initiation when overexpressed without being toxic in normal cells.…”

Stratégies génétiques, immunologiques et pharmacologiques au service d’une nouvelle génération de virus anticancéreux

“…Divers gènes proapoptotiques et cytotoxiques ont été incorporés dans les virus oncolytiques pour augmenter leur activité oncolytique. Par exemple, l'expression de TRAIL (tumor necrosis factor related apoptosis inducing ligand) et de l'interleukine 24 par des virus oncolytiques a permis d'améliorer l'efficacité de ces virus contre les cellules cancéreuses [17]. D'autres recherches ont conduit au développement de virus armés d'enzymes qui convertissent localement une prodrogue inactive en une substance toxique pour les cellules environnantes [18].…”

Homoharringtonine acts synergistically with SG235-TRAIL, a conditionally replicating adenovirus, in human leukemia cell lines

“…The construction of SG235-TRAIL has been described previously [13] . Plasmid pZD55-TRAIL was cotransfected with a serotype 35 adenovirus vector (pPE35) into 293 cells to generate the SG235-TRAIL by homologous recombination.…”

“…PBS was used as a control. The cell viability was determined by MTT assay as previously described [13] .…”

“…Furthermore, modifications of viral fiber, such as Ad5/11 and Ad5/F35 chimeric fibers, help to transduce type 5 adenovirus utilizing the Coxsackie-adenovirus recptor (CAR) as the primary receptor for viral internalization into cancer cells with low CAR expression levels [10][11][12] . We have previously shown that a CRAd with E1B-55 kDa deletion and Ad5/F35 chimeric fiber, which express exogenous apoptosis inducing gene tumor necrosis factor-related apoptosis-inducing ligand (SG235-TRAIL), effectively kills leukemic cells and reduces the growth of leukemic xenografts [13,14] . These results suggest that SG235-TRAIL virus might be envisaged for the treatment of leukemia.…”