The effect of promoter strength in adenoviral vectors containing herpes simplex virus thymidine kinase on cancer gene therapy in vitro and in vivo.
The use of adenoviral vectors to deliver the herpes simplex virus thymidine kinase (HSVtk) gene followed by treatment with the prodrug ganciclovir (GCV) has promise for a variety of applications where excess cell proliferation is detrimental such as treatment of tumors and vascular restenosis. Optimizing this system is thus an important goal. The purpose of this study was to determine if the induction of higher levels of HSVtk expression would augment the sensitivity to GCV. This was accomplished by generating adenoviral vectors that expressed HSVtk from promoters of different efficiencies (the CMV versus RSV promoters). Despite higher levels of HSVtk expression per cell with the CMV promoter, there was no significant enhancement of antitumor effects between RSV- and CMV-driven adenovirus vectors in in vitro and in vivo studies indicating that simply increasing HSVtk enzyme levels per cell above a minimal threshold level will not be effective in augmenting the HSVtk/GCV system. These results suggest that other strategies, e.g., the use of higher doses of GCV, augmentation of the "bystander effect," the generation of mutant HSVtk genes with higher substrate affinities, the discovery of improved vectors with increased transduction efficiencies, or the development of new prodrugs with higher affinities for HSVtk will therefore be needed to enhance therapeutic responses.
Elshami
A A
AA
Department of Medicine, University of Pennsylvania Medical Center, Philadelphia, USA.
Cook
J W
JW
Amin
K M
KM
Choi
H
H
Park
J Y
JY
Coonrod
L
L
Sun
J
J
Molnar-Kimber
K
K
Wilson
J M
JM
Kaiser
L R
LR
Albelda
S M
SM
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D009374:Neoplasms, Experimental / Q000235:genetics / Q000628:therapy*; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D018139:Simplexvirus / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D013937:Thymidine Kinase