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
Y1 - 2002
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.
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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 -