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Cell specific Cre-mediated activation of the diphtheria toxin gene in pituitary tumor: Potential for cytotoxic gene therapy

Authors
 Eun Jig Lee  ;  J. Larry Jameson 
Citation
 HUMAN GENE THERAPY, Vol.13(4) : 533-542, 2002 
Journal Title
 HUMAN GENE THERAPY 
ISSN
 1043-0342 
Issue Date
2002
MeSH
Adenoviridae ; Animals ; Cell Death/genetics ; Diphtheria Toxin/genetics* ; Gene Expression Regulation, Neoplastic ; Gene Transfer Techniques ; Genetic Therapy ; Genetic Vectors ; Growth Hormone/biosynthesis ; Growth Hormone/genetics ; Integrases/genetics* ; Mice ; Mice, Nude ; Mice, Transgenic ; Pituitary Neoplasms/genetics* ; Pituitary Neoplasms/metabolism ; Pituitary Neoplasms/pathology ; Pituitary Neoplasms/therapy ; Promoter Regions, Genetic ; Tumor Cells, Cultured ; Viral Proteins/genetics*
Abstract
Diphtheria toxin has been suggested for the treatment of malignant cancer. In this paper, we describe a strategy for targeting the expression of the diphtheria toxin gene to growth hormone (GH)-producing pituitary tumor cells using adenoviral vectors. We generated adenoviral vectors in which a stuffer DNA fragment, flanked by two loxP sequences, was placed between the GH or cytomegalovirus (CMV) promoters and the diphtheria toxin gene (GH-loxP-DT, and CMV-loxP-DT) or the beta-Gal gene (GH-loxP-Gal, and CMV-loxP-Gal). Co-infection of GH-loxP-DT with either CMV-Cre or GH-Cre induced cytotoxicity that was limited to GH4 cells. Little or no cytopathic effect was seen in GH4 cells infected with control viruses (CMV-loxP-Gal or GH-loxP-Gal with CMV-Cre or GH-Cre). To test the effectiveness of this strategy in vivo, GH4 cells were transplanted into nude mice. Intratumoral co-injection of adenoviruses carrying diphtheria toxin (GH-loxP-DT, and CMV-loxP-DT) and Cre recombinase (GH-Cre, and CMV-Cre) caused rapid regression of the transplanted GH4 tumors. These results indicate that Cre-mediated activation of a loxP-repressed form of the DT gene provides a useful strategy for targeted suicide gene therapy. This approach may be useful for GH-secreting adenomas and should be applicable to other neoplastic disorders
Full Text
http://online.liebertpub.com/doi/abs/10.1089/10430340252809829
DOI
10.1089/10430340252809829
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Lee, Eun Jig(이은직) ORCID logo https://orcid.org/0000-0002-9876-8370
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/144054
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