Abstract
The presence of severe hypoxia and necrosis in solid tumors offers the potential to apply an anaerobic bacterial enzyme/prodrug approach in cancer treatment. In this context the apathogenic C. acetobutylicum was genetically engineered to express and secrete E. coli cytosine deaminase (CDase). Considerable levels of functional cytosine deaminase were detected in lysates and supernatants of recombinant C acetobutylicum cultures. After administration of the recombinant Clostridium to rhabdomyosarcoma bearing rats used as a model, cytosine deaminase could be detected at the tumor site. Moreover, following administration of the vascular targeting agent combretastatin A-4 phosphate significantly increased levels of cytosine deaminase were detected at the tumor site as a consequence of enlarged tumor necrosis and subsequently improved growth of C. acetobutylicum. The results provide evidence for the potential application of Clostrisdium-based therapeutic protein transfer to tumors in anticancer therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antifungal Agents / pharmacology
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Antimetabolites, Antineoplastic / pharmacology
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Antineoplastic Agents, Phytogenic / pharmacology
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Clostridium / enzymology
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Clostridium / genetics*
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Cytosine Deaminase
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DNA Primers / chemistry
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Drug Delivery Systems
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Escherichia coli / enzymology
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Flucytosine / pharmacology
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Fluorouracil / pharmacology
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Genetic Therapy
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Genetic Vectors / genetics
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In Vitro Techniques
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Neoplasm Transplantation
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Nucleoside Deaminases / genetics*
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Nucleoside Deaminases / metabolism
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Plasmids
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Rats
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Recombinant Proteins / administration & dosage
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Recombinant Proteins / metabolism
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Recombinant Proteins / therapeutic use
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Rhabdomyosarcoma / enzymology
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Rhabdomyosarcoma / therapy*
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Skin Neoplasms / enzymology
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Skin Neoplasms / therapy*
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Stilbenes / pharmacology
Substances
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Antifungal Agents
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Antimetabolites, Antineoplastic
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Antineoplastic Agents, Phytogenic
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DNA Primers
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Recombinant Proteins
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Stilbenes
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Flucytosine
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Nucleoside Deaminases
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Cytosine Deaminase
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fosbretabulin
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Fluorouracil