title: MIA (melanoma inhibitory activity) promoter mediated tissue-specific suicide gene therapy of malignant melanoma.
abstract: Suicide gene therapy of malignant melanoma essentially requires efficient gene transfer and highly selective therapeutic gene expression. To achieve this, recombinant adeno-associated virus (rAAV) particles were constructed containing the tissue-specific promoter of the human melanoma inhibitory activity (hMIA) gene combined with four copies of the enhancer element of the murine tyrosinase gene. Three melanoma and one cervix carcinoma cell line were infected with rAAV particles carrying a reporter gene under control of the enhancer/hMIA promoter in order to determine transcriptional activity and specificity of this system. Viral particles containing the enhancer/hMIA promoter mediated reporter gene activity only in melanoma cells, whereas infection with a cytomegalovirus (CMV)-based promoter construct induced unspecific gene expression. Correspondingly, transient transduction with viral particles bearing the HSVtk gene under the control of the enhancer/MIA promoter elements followed by treatment with ganciclovir (GCV) resulted in growth inhibition only in melanoma cells, whereas the CMV promoter-based construct induced unspecific cytotoxicity. In vivo experiments in nude mice demonstrated that tumors originating from human melanoma cells disappeared after stable, but not transient transduction with vectors bearing the HSVtk gene under the control of the enhancer/hMIA promoter in response to GCV application. In face of higher transduction efficiency, these rAAV particles might therefore be a useful tool for suicide gene therapy of malignant melanoma.
authors.affiliation: Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, Heidelberg, Germany. f.schoensiegel@dkfz-heidelberg.de
authors.forename: Frank
authors.initials: F
authors.lastname: Schoensiegel
authors.forename: Annette
authors.initials: A
authors.lastname: Paschen
authors.forename: Stephanie
authors.initials: S
authors.lastname: Sieger
authors.forename: Helmut
authors.initials: H
authors.lastname: Eskerski
authors.forename: Walter
authors.initials: W
authors.lastname: Mier
authors.forename: Heike
authors.initials: H
authors.lastname: Rothfels
authors.forename: Juergen
authors.initials: J
authors.lastname: Kleinschmidt
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.forename: Uwe
authors.initials: U
authors.lastname: Haberkorn
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001972:Bromodeoxycytidine / Q000031:analogs & derivatives; D045744:Cell Line, Tumor; D002469:Cell Separation; D003001:Cloning, Molecular; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000229:Dependovirus / Q000235:genetics; D004742:Enhancer Elements, Genetic; D016326:Extracellular Matrix Proteins; D005260:Female; D005434:Flow Cytometry; D015774:Ganciclovir / Q000494:pharmacology; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008545:Melanoma / Q000235:genetics / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D008957:Models, Genetic; D014442:Monophenol Monooxygenase / Q000235:genetics; D009363:Neoplasm Proteins; D009368:Neoplasm Transplantation; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D018139:Simplexvirus / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D000998:Antiviral Agents; D016326:Extracellular Matrix Proteins; D007166:Immunosuppressive Agents; C090059:MIA protein, human; C513263:Mia protein, mouse; D009363:Neoplasm Proteins; D011506:Proteins; D003841:Deoxycytidine; D001972:Bromodeoxycytidine; C011288:ibacitabine; D014442:Monophenol Monooxygenase; D013937:Thymidine Kinase; D015774:Ganciclovir