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 β-Gal gene (GH-loxP-Gal, and CMV-loxP-Gal). Coinfection 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.
| Original language | English |
|---|---|
| Pages (from-to) | 533-542 |
| Number of pages | 10 |
| Journal | Human Gene Therapy |
| Volume | 13 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2002 Apr 6 |
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All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Molecular Biology
- Genetics
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Cell-specific Cre-mediated activation of the diphtheria toxin gene in pituitary tumor cells : Potential for cytotoxic gene therapy. / Lee, Eun Jig; Jameson, J. Larry.
In: Human Gene Therapy, Vol. 13, No. 4, 06.04.2002, p. 533-542.Research output: Contribution to journal › Article
TY - JOUR
T1 - Cell-specific Cre-mediated activation of the diphtheria toxin gene in pituitary tumor cells
T2 - Potential for cytotoxic gene therapy
AU - Lee, Eun Jig
AU - Jameson, J. Larry
PY - 2002/4/6
Y1 - 2002/4/6
N2 - 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 β-Gal gene (GH-loxP-Gal, and CMV-loxP-Gal). Coinfection 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.
AB - 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 β-Gal gene (GH-loxP-Gal, and CMV-loxP-Gal). Coinfection 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.
UR - http://www.scopus.com/inward/record.url?scp=0036209722&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036209722&partnerID=8YFLogxK
U2 - 10.1089/10430340252809829
DO - 10.1089/10430340252809829
M3 - Article
C2 - 11874631
AN - SCOPUS:0036209722
VL - 13
SP - 533
EP - 542
JO - Human Gene Therapy
JF - Human Gene Therapy
SN - 1043-0342
IS - 4
ER -