Induced expression of the conditionally cytotoxic herpes simplex virus thymidine kinase gene by means of a parvoviral regulatory circuit.
As a step toward the achievement of targeted expression of toxic genes, we have established a model system using the selective trans-activation of the late promoter P38 of Minute Virus of Mice (MVMp) by the parvoviral nonstructural protein NS-1. The conditionally toxic herpes simplex virus type 1 thymidine kinase (tk) gene (HSV1-tk) was cloned under the control of the P38 promoter and transfected into NIH-3T3 TK- cells. Treatment of the stably transfected cells with acyclovir (ACV) followed by infection with MVMp reduced cell survival by 3.5- to 5-fold compared to the toxic effects of ACV or MVMp alone. These results indicate that it should be possible to combine the genuine cytopathic action of parvoviruses with a specific activation of toxic genes driven by parvoviral promoters, to achieve the targeted destruction of parvovirus-expressing (in particular tumor) cells.
Koering
C E
CE
Unité d'Oncologie Moléculaire, Institut Pasteur de Lille, Centre National de la Recherche Scientifique URA, France.
Dupressoir
T
T
Plaza
S
S
Stehelin
D
D
Rommelaere
J
J
D016475:3T3 Cells / Q000187:drug effects; D000212:Acyclovir / Q000494:pharmacology; D000818:Animals; D016923:Cell Death; D003588:Cytopathogenic Effect, Viral; D015967:Gene Expression Regulation, Viral; D005822:Genetic Vectors; D051379:Mice; D008915:Minute Virus of Mice / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis* / Q000235:genetics; D018139:Simplexvirus / Q000201:enzymology* / Q000235:genetics; D013937:Thymidine Kinase / Q000096:biosynthesis* / Q000235:genetics; D015533:Transcriptional Activation; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000502:physiology*; D014764:Viral Proteins / Q000096:biosynthesis* / Q000235:genetics
C081367:NS1 protein, minute virus of mice; D011993:Recombinant Fusion Proteins; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; D013937:Thymidine Kinase; D000212:Acyclovir