Construction of gene therapy vectors targeting thyroid cells: enhancement of activity and specificity with histone deacetylase inhibitors and agents modulating the cyclic adenosine 3',5'-monophosphate pathway and demonstration of activity in follicular and anaplastic thyroid carcinoma cells.
Thyroid carcinoma accounts for the majority of deaths from endocrine cancers. Although effective therapies exist for well differentiated tumors, the treatment options for poorly differentiated and anaplastic tumors are much less effective. In the present study we demonstrate that the thyroglobulin (Tg) promoter can be used to direct specific expression of either luciferase or thymidine kinase in thyroid cancer cells. Furthermore, using a putative enhancer element for the Tg gene, the activity of the Tg promoter in and its specificity for thyroid cells were enhanced. In transient transfectants or in stably transfected thyroid carcinoma cells, treatment with the histone deacetylase inhibitors, depsipeptide (FR9012228) and sodium butyrate, alone or in combination with 8-bromo-cAMP, resulted in further enhancement. In experiments in which the herpes simplex virus thymidine kinase (HSV-TK) gene was driven by the Tg promoter and the putative enhancer, HSV-TK expression and ganciclovir sensitivity were augmented. Similar results were obtained in two cell lines derived from a follicular thyroid carcinoma and in two anaplastic thyroid carcinoma cell lines. In summary, we report the construction of a suicide HSV-TK vector with preferential toxicity for thyroid cells. The results in anaplastic thyroid carcinoma cells suggest that it may be of use in the full spectrum of thyroid malignancies.
Kitazono
M
M
Medicine Branch, DCS, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. kita@box-k.nih.gov
Chuman
Y
Y
Aikou
T
T
Fojo
T
T
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D018263:Adenocarcinoma, Follicular / Q000188:drug therapy / Q000473:pathology; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D002087:Butyrates / Q000494:pharmacology; D002277:Carcinoma / Q000188:drug therapy / Q000473:pathology; D000242:Cyclic AMP / Q000502:physiology*; D047630:Depsipeptides; D004742:Enhancer Elements, Genetic; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008156:Luciferases / Q000235:genetics; D010456:Peptides, Cyclic; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018139:Simplexvirus / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics; D013954:Thyroglobulin / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014162:Transfection / Q000379:methods; D014407:Tumor Cells, Cultured
D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D002087:Butyrates; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; D015124:8-Bromo Cyclic Adenosine Monophosphate; D013954:Thyroglobulin; C087123:romidepsin; D000242:Cyclic AMP; D008156:Luciferases; D013937:Thymidine Kinase