Chemotherapeutic tumour targeting using clostridial spores |
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Authors: | Nigel P Minton Margaret L Mauchline Marylin J Lemmon John K Brehm Mary Fox NPaul Michael Amato Giaccia JMartin Brown |
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Institution: | Department of Molecular Microbiology, Research Division, Centre for Applied Microbiology and Research, Porton Down, Salisbury, Wiltshire SP4 0JG, UK;Department of Radiation Oncology, Division of Radiation Biology, Stanford University School of Medicine, Stanford, CA 94305-5468, USA |
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Abstract: | Abstract: The toxicity associated with conventional cancer chemotherapy is primarily due to a lack of specificity for tumour cells. In contrast, intravenously injected clostridial spores exhibit a remarkable specificity for tumours. This is because, following their administration, clostridial spores become exclusively localised to, and germinate in, the hypoxic/necrotic tissue of tumours. This unique property could be exploited to deliver therapeutic agents to tumours. In particular, genetic engineering could be used to endow a suitable clostridial host with the capacity to produce an enzyme within the tumour which can metabolise a systematically introduced, non-toxic prodrug into a toxic metabolite. The feasibility of this strategy (clostridial-directed enzyme prodrug therapy, CDEPT) has been demonstrated by cloning the Escherichia coli B gene encoding nitroreductase (an enzyme which converts the prodrug CB1954 to a highly toxic bifunctional alkylating agent) into a clostridial expression vector and introducing the resultant plasmid into Clostridium beijerinckii (formerly C. acetobutylicum ) NCIMB 8052. The gene was efficiently expressed, with recombinant nitroreductase representing 8% of the cell soluble protein. Following the intravenous injection of the recombinant spores into mice, tumour lysates have been shown, by Western blots, to contain the E. coli -derived enzyme. |
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Keywords: | Clostridium spp Sporulation Oncolysis Enzyme prodrug therapy Nitroreductase |
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