title: Activation of multiple chemotherapeutic prodrugs by the natural enzymolome of tumour-localised probiotic bacteria.
abstract: Some chemotherapeutic drugs (prodrugs) require activation by an enzyme for efficacy. We and others have demonstrated the ability of probiotic bacteria to grow specifically within solid tumours following systemic administration, and we hypothesised that the natural enzymatic activity of these tumour-localised bacteria may be suitable for activation of certain such chemotherapeutic drugs. Several wild-type probiotic bacteria; Escherichia coli Nissle, Bifidobacterium breve, Lactococcus lactis and Lactobacillus species, were screened against a panel of popular prodrugs. All strains were capable of activating at least one prodrug. E. coli Nissle 1917 was selected for further studies because of its ability to activate numerous prodrugs and its resistance to prodrug toxicity. HPLC data confirmed biochemical transformation of prodrugs to their toxic counterparts. Further analysis demonstrated that different enzymes can complement prodrug activation, while simultaneous activation of multiple prodrugs (CB1954, 5-FC, AQ4N and Fludarabine phosphate) by E. coli was confirmed, resulting in significant efficacy improvement. Experiments in mice harbouring murine tumours validated in vitro findings, with significant reduction in tumour growth and increase in survival of mice treated with probiotic bacteria and a combination of prodrugs. These findings demonstrate the ability of probiotic bacteria, without the requirement for genetic modification, to enable high-level activation of multiple prodrugs specifically at the site of action.
authors.affiliation: Cork Cancer Research Centre, University College Cork, Cork, Ireland.
authors.forename: Panos
authors.initials: P
authors.lastname: Lehouritis
authors.affiliation: Cork Cancer Research Centre, University College Cork, Cork, Ireland.
authors.forename: Michael
authors.initials: M
authors.lastname: Stanton
authors.affiliation: Department of Chemistry and Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland.
authors.forename: Florence O
authors.initials: FO
authors.lastname: McCarthy
authors.affiliation: Cork Cancer Research Centre, University College Cork, Cork, Ireland.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Jeavons
authors.affiliation: Cork Cancer Research Centre, University College Cork, Cork, Ireland. Electronic address: m.tangney@ucc.ie.
authors.forename: Mark
authors.initials: M
authors.lastname: Tangney
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000008:administration & dosage / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001388:Aziridines / Q000008:administration & dosage / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000378:metabolism*; D001644:Bifidobacterium / Q000201:enzymology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D004798:Enzymes; D004926:Escherichia coli / Q000201:enzymology; D005260:Female; D007778:Lactobacillus / Q000201:enzymology; D017045:Lactococcus / Q000201:enzymology; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019936:Probiotics; D011355:Prodrugs / Q000008:administration & dosage* / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D001084:Vidarabine Phosphate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D000880:Anthraquinones; D000970:Antineoplastic Agents; D001388:Aziridines; D001426:Bacterial Proteins; D004798:Enzymes; D011355:Prodrugs; D001084:Vidarabine Phosphate; C042382:fludarabine phosphate; C094428:AQ4N; C100099:tretazicar
keywords: Cancer; Chemotherapy; GDEPT; Targeting; Therapy