title: Preclinical study on combined chemo- and nonviral gene therapy for sensitization of melanoma using a human TNF-alpha expressing MIDGE DNA vector.
abstract: Nonviral gene therapy represents a realistic option for clinical application in cancer treatment. This preclinical study demonstrates the advantage of using the small-size MIDGE(®) DNA vector for improved transgene expression and therapeutic application. This is caused by significant increase in transcription efficiency, but not by increased intracellular vector copy numbers or gene transfer efficiency. We used the MIDGE-hTNF-alpha vector for high-level expression of hTNF-alpha in vitro and in vivo for a combined gene therapy and vindesine treatment in human melanoma models. The MIDGE vector mediated high-level hTNF-alpha expression leads to sensitization of melanoma cells towards vindesine. The increased efficacy of this combination is mediated by remarkable acceleration and increase of initiator caspase 8 and 9 and effector caspase 3 and 7 activation. In the therapeutic approach, the nonviral intratumoral in vivo jet-injection gene transfer of MIDGE-hTNF-alpha in combination with vindesine causes melanoma growth inhibition in association with increased apoptosis in A375 cell line or patient derived human melanoma xenotransplant (PDX) models. This study represents a proof-of-concept for an anticipated phase I clinical gene therapy trial, in which the MIDGE-hTNF-alpha vector will be used for efficient combined chemo- and nonviral gene therapy of malignant melanoma.
authors: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. Electronic address: dennis.kobelt@mdc-berlin.de.
authors: Dennis
authors: D
authors: Kobelt
authors: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany; Experimental and Clinical Research Center, Charité University Medicine, Berlin, Germany.
authors: Jutta
authors: J
authors: Aumann
authors: Mologen AG, Berlin, Germany.
authors: Manuel
authors: M
authors: Schmidt
authors: Foundation Institute Molecular Biology and Bioinformatics, Freie Universität Berlin, Berlin, Germany.
authors: Burghardt
authors: B
authors: Wittig
authors: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors: Iduna
authors: I
authors: Fichtner
authors: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors: Diana
authors: D
authors: Behrens
authors: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors: Margit
authors: M
authors: Lemm
authors: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany; Experimental and Clinical Research Center, Charité University Medicine, Berlin, Germany.
authors: Greta
authors: G
authors: Freundt
authors: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany; Charité Comprehensive Cancer Center, Berlin, Germany.
authors: Peter M
authors: PM
authors: Schlag
authors: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany; Experimental and Clinical Research Center, Charité University Medicine, Berlin, Germany. Electronic address: wowalt@mdc-berlin.de.
authors: Wolfgang
authors: W
authors: Walther
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004247:DNA / Q000235:genetics / Q000627:therapeutic use*; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use*; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D014162:Transfection; D019076:Transgenes; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D014751:Vindesine / Q000627:therapeutic use
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D014751:Vindesine
keywords: Cancer; Gene therapy; Melanoma; Nonviral gene transfer; TNF-alpha