Concomitant use of Ad5/35 chimeric oncolytic adenovirus with TRAIL gene and taxol produces synergistic cytotoxicity in gastric cancer cells.
Chimeric adenoviral vectors possessing fiber derived from human adenovirus subgroup B (Ad35) have been developed for their high infection efficiency in cell types which are refractory to adenovirus serotype 5 (Subgroup C). The present study constructed an E1B-deleted chimeric oncolytic adenovirus, SG235-TRAIL, which carries a human TRAIL gene expression cassette and whose fiber shaft and knob domains are from serotype Ad35. It was found that SG235-TRAIL preferentially replicated in gastric cancer cell lines, SGC-7901 and BGC-823 compared to in normal human fibroblast BJ cells. Also, when compared with a replication-deficient chimeric vector Ad5/35-TRAIL, SG235-TRAIL mediated a higher level of the transgene expression via viral replication in the cancer cells. Further, because of the more efficient cell-entry and infection, SG235-TRAIL induced stronger cell apoptosis than the Ad5 CRAD vector, ZD55-TRAIL. In addition, SG235-TRAIL in combination with the chemotherapeutic drug, taxol, produced a synergistic cytotoxic effect in cancer cells in vitro without causing significant toxicity to normal cells. In the gastric tumor xenograft mouse model, intratumoral SG235-TRAIL injection produced a significant antitumor effect 14 days after treatment. Pathological examination demonstrated TRAIL expression and associated apoptosis in majority of SG235-TRAIL-treated tumor cells. These results suggest that SG235-TRAIL is a potential novel, efficient anti-cancer agent, and in combination with taxol, it would be even more useful with considerably low toxic side effects.
Chen
Lin
L
Department of General Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Chen
Dongfeng
D
Gong
Mouchun
M
Na
Manli
M
Li
Linfang
L
Wu
Hongping
H
Jiang
Lihua
L
Qian
Yanzhen
Y
Fang
Guoen
G
Xue
Xuchao
X
D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D000260:Adenoviruses, Human / Q000145:classification / Q000235:genetics* / Q000502:physiology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000821:virology; D003131:Combined Modality Therapy; D003673:Defective Viruses / Q000502:physiology; D005347:Fibroblasts / Q000821:virology; D005813:Genes, Synthetic; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D017239:Paclitaxel / Q000008:administration & dosage / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000627:therapeutic use; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000627:therapeutic use*; D019076:Transgenes; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D011993:Recombinant Fusion Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D017239:Paclitaxel