Chemotherapeutic tumour targeting using clostridial spores.
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.
Minton
N P
NP
Department of Molecular Microbiology, Centre for Applied Microbiology and Research, Porton Down, Salisbury, Wiltshire, UK.
Mauchline
M L
ML
Lemmon
M J
MJ
Brehm
J K
JK
Fox
M
M
Michael
N P
NP
Giaccia
A
A
Brown
J M
JM
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D001388:Aziridines / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D001711:Biotransformation; D003013:Clostridium / Q000235:genetics*; D004274:DNA, Recombinant; D016503:Drug Delivery Systems / Q000379:methods*; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy*; D009601:Nitroreductases / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D011355:Prodrugs / Q000627:therapeutic use; D013171:Spores, Bacterial
D000970:Antineoplastic Agents; D001388:Aziridines; D004274:DNA, Recombinant; D011355:Prodrugs; C100099:tretazicar; D009601:Nitroreductases