Tumor-targeting prodrug-activating bacteria for cancer therapy

Cancer Gene Ther. 2008 Jun;15(6):393-401. doi: 10.1038/cgt.2008.10. Epub 2008 Mar 28.

Abstract

Increasing the specificity of chemotherapy may improve the efficacy of cancer treatment. Toward this aim, we developed a strain of bacteria to express enzymes for selective prodrug activation and non-invasive imaging in tumors. beta-glucuronidase and the luxCDABE gene cluster were expressed in the DH5alpha strain of Escherichia coli to generate DH5alpha-lux/betaG. These bacteria emitted light for imaging and hydrolyzed the glucuronide prodrug 9ACG to the topoisomerase I inhibitor 9-aminocamptothecin (9AC). By optical imaging, colony-forming units (CFUs) and staining for betaG activity, we found that DH5alpha-lux/betaG preferentially localized and replicated within CL1-5 human lung tumors in mice. The intensity of luminescence, CFU and betaG activity increased with time, indicating bacterial replication occurred in tumors. In comparison with DH5alpha-lux/betaG, 9AC or 9ACG treatment, combined systemic administration of DH5alpha-lux/betaG followed by 9ACG prodrug treatment significantly (P<0.005) delayed the growth of CL1-5 tumors. Our results demonstrate that prodrug-activating bacteria may be useful for selective cancer chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacteria / genetics
  • Bacteria / metabolism*
  • Glucuronidase / genetics
  • Glucuronidase / metabolism
  • Glucuronides / metabolism
  • Humans
  • Models, Biological
  • Neoplasms / microbiology
  • Neoplasms / pathology
  • Neoplasms / therapy*
  • Prodrugs / metabolism
  • Prodrugs / therapeutic use*

Substances

  • Glucuronides
  • Prodrugs
  • Glucuronidase