Ganciclovir-induced ablation non-proliferating thyrocytes expressing herpesvirus thymidine kinase occurs by p53-independent apoptosis.
In adult mice of the transgenic strain TG66.19, in which expression of herpes simplex type 1 virus thymidine kinase (HSVI-TK) is driven in thyrocytes from the thyroglobulin promoter, the drug Ganciclovir causes the death (ablation) of thyrocytes. Ablation occurred in the absence of thyrocyte proliferation or nuclear DNA synthesis, but was accompanied by transient expression of proliferating cell nuclear antigen and the dying thyrocytes exhibited the ultrastructural features of apoptosis. Control experiments show that the apoptosis is a result of the production of Ganciclovir phosphates in thyrocytes that express HSV1-TK. However, cell death was not dependent upon the presence of a functional copy of the oncosuppressor gene p53. We conclude that the apoptosis is probably not mediated by induction of DNA damage and occurs via a pathway that is independent of p53. The fact that Ganciclovir phosphate can kill cells by a p53-independent apoptotic pathway is encouraging in relation to tumour ablation by methods based on transfection with HSV1-tk genes and administration of Ganciclovir.
Wallace
H
H
Centre for Genome Research, University of Edinburgh, UK.
Clarke
A R
AR
Harrison
D J
DJ
Hooper
M L
ML
Bishop
J O
JO
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D002417:Cattle; D002455:Cell Division; D004247:DNA / Q000096:biosynthesis; D004261:DNA Replication; D004272:DNA, Mitochondrial / Q000096:biosynthesis; D004790:Enzyme Induction; D005260:Female; D015774:Ganciclovir / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism*; D013954:Thyroglobulin / Q000235:genetics*; D013961:Thyroid Gland / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D004272:DNA, Mitochondrial; D018809:Proliferating Cell Nuclear Antigen; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D004247:DNA; D013954:Thyroglobulin; D013937:Thymidine Kinase; D015774:Ganciclovir