Efficient and selective tumor cell lysis and induction of apoptosis in melanoma cells by a conditional replication-competent CD95L adenovirus.
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.
Fecker
Lothar F
LF
Department of Dermatology and Allergy, HTCC - Skin Cancer Center Charité, Charité-Universitätsmedizin Berlin.
Schmude
Magdalena
M
Jost
Stefanie
S
Hossini
Amir M
AM
Picó
Almudena Hurtado
AH
Wang
Xiaomin
X
Schwarz
Constanze
C
Fechner
Henry
H
Eberle
Jürgen
J
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*
D017500:Adenovirus E1A Proteins; D053222:Fas Ligand Protein; D004318:Doxycycline