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. Cancer Gene Therapy (2001) 8, 294–297
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Acknowledgements
G. Reysset (Institut Pasteur, Paris) is acknowledged for his help on the transformation of C. acetobutylicum NI 4082. We also appreciate the stimulating discussions with Ernst de Bruijn from the Oncology Department (University Hospital Gasthuisberg, Leuven). We acknowledge the financial support from “Het Fonds voor Wetenschappelijk Onderzoek-Vlaanderen,” “Het K.U. Leuven Onderzoeksfonds,” and “VIS (Verkennende Internationale Samenwerking).” Jan Theys and Sandra Nuyts are research fellows of “IWT” (Vlaams Instituut voor de bevordering van het Wetenschappelijk-Technologisch Onderzoek in de Industrie).
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Theys, J., Landuyt, W., Nuyts, S. et al. Specific targeting of cytosine deaminase to solid tumors by engineered Clostridium acetobutylicum. Cancer Gene Ther 8, 294–297 (2001). https://doi.org/10.1038/sj.cgt.7700303
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DOI: https://doi.org/10.1038/sj.cgt.7700303
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