Intratumoral gene delivery of anti-cathepsin L single-chain variable fragment by lentiviral vector inhibits tumor progression induced by human melanoma cells.
We previously demonstrated that the switch from non- to highly tumorigenic phenotype of human melanoma cells is directly related to procathepsin L secretion, which increased cell resistance to complement-mediated cell lysis. Involvement of procathepsin L secretion in tumor growth was clearly demonstrated by three different strategies: (1) inhibition of secreted procathepsin L activity; (2) increase of procathepsin L secretion; and (3) inhibition of procathepsin L secretion. This latter strategy was triggered by intracellular expression of anti-human cathepsin L single-chain variable fragment (ScFv). These previous experiments were performed by processing melanoma cells before their injection into nude mice. We herein designed a new lentiviral vector in which this anti-cathepsin L ScFv was cloned. This lentiviral vector was optimized to allow the highest intracellular expression of anti-cathepsin L ScFv in transduced melanoma cells. In these transduced cells, procathepsin L secretion was strongly inhibited. In addition, injection of this anti-cathepsin L ScFv lentiviral vector into tumors already induced in nude mice inhibited tumor growth and associated angiogenesis. This is the first report to demonstrate that targeting procathepsin L secretion with anti-cathepsin L ScFv lentiviral construct constitutes a new gene therapy in the challenge to inhibit the growth of tumors induced by human melanoma cells.
Frade
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R
INSERM U.672 (former U.354), Immunochemistry of Cell Regulations and Viral Interactions, Bâtiment G8, Evry Cedex, France. raymond.frade@inserm.fr
Rousselet
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N
Jean
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D
D000818:Animals; D056668:Cathepsin L; D002403:Cathepsins / Q000276:immunology / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000494:pharmacology*; D016086:Lentivirus / Q000235:genetics*; D008297:Male; D008545:Melanoma / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D011994:Recombinant Proteins / Q000494:pharmacology; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous
D004792:Enzyme Precursors; D007135:Immunoglobulin Variable Region; D011994:Recombinant Proteins; D002403:Cathepsins; C063905:procathepsin L; D056668:Cathepsin L