A hypoxia-regulated adeno-associated virus vector for cancer-specific genetherapy

Citation
Hj. Ruan et al., A hypoxia-regulated adeno-associated virus vector for cancer-specific genetherapy, NEOPLASIA, 3(3), 2001, pp. 255-263
Citations number
35
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Onconogenesis & Cancer Research
Journal title
NEOPLASIA
ISSN journal
1522-8002 → ACNP
Volume
3
Issue
3
Year of publication
2001
Pages
255 - 263
Database
ISI
SICI code
1522-8002(200105/06)3:3<255:AHAVVF>2.0.ZU;2-K
Abstract
The presence of hypoxic cells in human brain tumors is an important factor leading to resistance to radiation therapy. However, this physiological dif ference between normal tissues and tumors also provides the potential for d esigning cancer-specific gene therapy. We compared the increase of gene exp ression under anoxia (<0.01% oxygen) produced by 3, 6, and 9 copies of hypo xia-responsive elements (HRE) from the erythropoietin gene (Epo), which are activated through the transcriptional complex hypoxia-inducible factor 1 ( HIF-1). Under anoxic conditions, nine copies of HIRE (9XHRE) yielded 27- to 37-fold of increased gene expression in U-251 MG and U-87 MG human brain t umor cell lines. Under the less hypoxic conditions of 0.3% and 1% oxygen, g ene activation by 9XHRE increased expression 11- to 18-fold in these cell l ines. To generate a recombinant adeno-associated virus (rAAV) in which the transgene can be regulated by hypoxia, we inserted the DNA fragment contain ing 9XHRE and the LacZ reporter gene into an AAV vector. Under anoxic condi tions, this vector produced 79- to 110-fold increase in gene expression. We believe this hypoxia-regulated rAAV vector will provide a useful delivery vehicle for cancer-specific gene therapy.