Open AccessChemotherapeutic tumour targeting using clostridial spores
Author(s) -
Minton Nigel P,
Mauchline Margaret L,
Lemmon Marylin J,
Brehm John K,
Fox Mary,
Michael N.Paul,
Giaccia Amato,
Brown J.Martin
Publication year - 1995
Publication title -
fems microbiology reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.91
H-Index - 212
eISSN - 1574-6976
pISSN - 0168-6445
DOI - 10.1111/j.1574-6976.1995.tb00219.x
Subject(s) - nitroreductase , prodrug , biology , clostridium acetobutylicum , microbiology and biotechnology , clostridium beijerinckii , clostridium , recombinant dna , enzyme , plasmid , escherichia coli , rifamycin , biochemistry , antibiotics , bacteria , gene , butanol , genetics , ethanol
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.