title: Efficient and selective tumor cell lysis and induction of apoptosis in melanoma cells by a conditional replication-competent CD95L adenovirus.
abstract: The high mortality of melanoma demands the development of new strategies, and gene therapy may be considered provided improvements in efficacy and selectivity. Overexpression of the death ligand CD95L/FasL has been shown in previous studies as highly effective for apoptosis induction in melanoma cells. For efficient and selective targeting of melanoma, a conditional replication-competent adenoviral vector was constructed (Ad5-FFE-02), which drives CD95L expression by a tetracycline-inducible promoter. For restricting its replication to melanoma cells, the adenoviral E1A gene is controlled by a tyrosinase-derived promoter. Furthermore, adenoviral E1B was deleted and a mutated E1A was used to preferentially support replication in tumor cells. Proving its high selectivity and efficiency, strong expression of E1A and doxycycline-dependent induction of CD95L were characteristic for tyrosinase-positive melanoma cells after Ad5-FFE-02 transduction, whereas absent in non-melanoma cell lines. Importantly, Ad5-FFE-02-mediated cell lysis was restricted to melanoma cells, and induction of apoptosis was found only in tyrosinase and CD95 expressing cells. Finally, the combination of adenoviral replication and CD95L-mediated apoptosis resulted in an enhanced repression of melanoma cell growth. This new adenoviral vector may provide a basis for an efficient targeting of melanoma.
authors.affiliation: Department of Dermatology and Allergy, HTCC - Skin Cancer Center Charité, Charité-Universitätsmedizin Berlin.
authors.forename: Lothar F
authors.initials: LF
authors.lastname: Fecker
authors.forename: Magdalena
authors.initials: M
authors.lastname: Schmude
authors.forename: Stefanie
authors.initials: S
authors.lastname: Jost
authors.forename: Amir M
authors.initials: AM
authors.lastname: Hossini
authors.forename: Almudena Hurtado
authors.initials: AH
authors.lastname: Picó
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Wang
authors.forename: Constanze
authors.initials: C
authors.lastname: Schwarz
authors.forename: Henry
authors.initials: H
authors.lastname: Fechner
authors.forename: Jürgen
authors.initials: J
authors.lastname: Eberle
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology; D017500:Adenovirus E1A Proteins / Q000378:metabolism; D017209:Apoptosis; D045744:Cell Line, Tumor; D004318:Doxycycline / Q000494:pharmacology; D053222:Fas Ligand Protein / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D010957:Plasmids; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D014779:Virus Replication / Q000502:physiology*
chemical_list: D017500:Adenovirus E1A Proteins; D053222:Fas Ligand Protein; D004318:Doxycycline