Chemotherapeutic tumour targeting using clostridial spores
| Autor: | Mary E. Fox, John K. Brehm, Margaret Lamble Mauchline, Nigel P. Minton, J. Martin Brown, N. Paul Michael, Marylin J Lemmon, Amato J. Giaccia |
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| Rok vydání: | 1995 |
| Předmět: |
Aziridines
DNA Recombinant Antineoplastic Agents Biology medicine.disease_cause Microbiology law.invention Mice Nitroreductase Drug Delivery Systems Plasmid law Neoplasms medicine Animals Prodrugs Escherichia coli Biotransformation Clostridium Spores Bacterial chemistry.chemical_classification Expression vector Nitroreductases Prodrug biology.organism_classification Infectious Diseases Enzyme Clostridium beijerinckii Biochemistry chemistry Recombinant DNA |
| Zdroj: | FEMS Microbiology Reviews. 17:357-364 |
| ISSN: | 1574-6976 |
| DOI: | 10.1111/j.1574-6976.1995.tb00219.x |
| Popis: | 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 systemically 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. |
| Databáze: | OpenAIRE |
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