Oncolytic effects of adenovirus mutant capable of replicating in hypoxic and normoxic regions of solid tumor.
Solid tumors contain normoxic and hypoxic regions depending on the distance from the capillary. Normal cells may also be exposed to hypoxia under certain physiological conditions. Tumor hypoxia has been shown to associate strongly with tumor propagation and malignant progression. Hypoxia-inducible factor (HIF)-1alpha is stable under hypoxia and induces transcription of target genes by binding to the hypoxia-response element (HRE). Here we investigated the oncolytic effects of a novel adenovirus mutant with a deleted E1B55 gene (Ad.Delta55.HRE), in which the expression of E1A, which is essential for adenoviral replication, is regulated under the control of an HRE-expression system. Ad.Delta55.HRE expressed E1A under normoxia and more E1A under hypoxia and exhibited oncolytic effects on various cultured tumor cells, but its cytotoxic effect is relatively attenuated in normal fibroblast cells under normoxic and hypoxic conditions. Ad.Delta55.HRE lysed Huh-7 hepatoma cells stably expressing HIF-1alpha more effectively compared to parental cells. Ad.Delta55.HRE treatment exhibited significant antitumor activity in PC-3 prostate- and MDA-MB-435 breast tumor-bearing nude mice in which HIF-1alpha protein was immunohistochemically detected. The E1A and hexon proteins of adenovirus were immunostained in MDA-MB-435 xenografts after Ad.Delta55.HRE treatment, suggestive of viral replication. Our results suggest that Ad.Delta55.HRE may be useful for the treatment of solid tumors.
Cho
Won-Kyung
WK
Gene Therapy Research Unit/Cell Biology Laboratory, Korea Research Institute of Bioscience and Biotechnology, Yusong, Daejeon 305-333, Republic of Korea.
Seong
Young Rim
YR
Lee
Yeune Hee
YH
Kim
Min Ji
MJ
Hwang
Kyung-Sun
KS
Yoo
Jinsang
J
Choi
Seeyoung
S
Jung
Cho-Rok
CR
Im
Dong-Soo
DS
D000256:Adenoviridae / Q000235:genetics*; D017500:Adenovirus E1A Proteins / Q000032:analysis / Q000235:genetics*; D017501:Adenovirus E1B Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D036022:Capsid Proteins / Q000032:analysis; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival; D017353:Gene Deletion; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000628:therapy*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020218:Response Elements / Q000235:genetics; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins; D036022:Capsid Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; C018315:hexon capsid protein, Adenovirus