Eliminating established tumor in nu/nu nude mice by a tumor necrosis factor-alpha-related apoptosis-inducing ligand-armed oncolytic adenovirus.
OBJECTIVE
The tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) and oncolytic viruses have recently been investigated extensively for cancer therapy. However, preclinical and clinical studies have revealed that their clinical application is hampered by either weak anticancer activity or systemic toxicity. We examined whether the weaknesses of the two strategies can be overcome by integrating the TRAIL gene into an oncolytic vector.


METHODS
We constructed a TRAIL-expressing oncolytic adenovector designated as Ad/TRAIL-E1. The expression of both the TRAIL and viral E1A genes is under the control of a synthetic promoter consisting of sequences from the human telomerase reverse transcriptase promoter and a minimal cytomegalovirus early promoter. The transgene expression, apoptosis induction, viral replication, antitumor activity, and toxicity of Ad/TRAIL-E1 were determined in vitro and in vivo in comparison with control vectors.


RESULTS
Ad/TRAIL-E1 elicited enhanced viral replication and/or stronger oncolytic effect in vitro in various human cancer cell lines than a TRAIL-expressing, replication-defective adenovector or an oncolytic adenovector-expressing green fluorescent protein. Intralesional administration of Ad/TRAIL-E1 eliminated all s.c. xenograft tumors established from a human non-small cell lung cancer cell line, H1299, on nu/nu nude mice, resulting in long-term, tumor-free survival. Furthermore, we found no treatment-related toxicity.


CONCLUSIONS
Viral replication and antitumor activity of oncolytic adenovirus can be enhanced by the TRAIL gene and Ad/TRAIL-E1 could become a potent therapeutic agent for cancer therapy.
Dong
Fengqin
F
Department of Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, USA, and Department of Metabolism and Endocrinology, The First Affiliated Hospital, Zhejiang University, Hangzhou, People's Republic of China.
Wang
Li
L
Davis
John J
JJ
Hu
Wenxian
W
Zhang
Lidong
L
Guo
Wei
W
Teraishi
Fuminori
F
Ji
Lin
L
Fang
Bingliang
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000628:therapy*; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007279:Injections, Subcutaneous; D008175:Lung Neoplasms / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013329:Structure-Activity Relationship; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000235:genetics* / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D053221:TNF-Related Apoptosis-Inducing Ligand