CHEMOTHERAPEUTIC TUMOR TARGETING USING CLOSTRIDIAL SPORES

The toxicity associated with conventional cancer chemotherapy is prima rily due to a lack of specificity for tumour cells. In contrast, intra venously injected clostridial spores exhibit a remarkable specificity for tumours. This is because, following their administration, clostrid ial spores become exclusively localised to, and germinate in, the hypo xic/necrotic tissue of tumours. This unique property could be exploite d to deliver therapeutic agents to tumours. In particular, genetic eng ineering could be used to endow a suitable clostridial host with the c apacity to produce an enzyme within the tumour which can metabolise a systemically introduced, non-toxic prodrug into a toxic metabolite. Th e feasibility of this strategy (clostridial-directed enzyme prodrug th erapy, CDEPT) has been demonstrated by cloning the Escherichia coli B gene encoding nitroreductase (an enzyme which converts the prodrug CB1 954 to a highly toxic bifunctional alkylating agent) into a clostridia l expression vector and introducing the resultant plasmid into Clostri dium beijerinckii (formerly C, acetobutylicum) NCIMB 8052. The gene wa s 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.