Tumor-targeting prodrug-activating bacteria for cancer therapy

• Published in: Cancer gene therapy Vol. 15; no. 6; pp. 393 - 401
• Main Authors: Cheng, C-M, Lu, Y-L, Chuang, K-H, Hung, W-C, Shiea, J, Su, Y-C, Kao, C-H, Chen, B-M, Roffler, S, Cheng, T-L
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2008; Nature Publishing Group
• Subjects: Animals; Bacteria; Bacteria - genetics; Bacteria - metabolism; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer therapies; Care and treatment; Chemotherapy; DNA topoisomerase; Escherichia coli; Gene Expression; Gene Therapy; Glucuronidase - genetics; Glucuronidase - metabolism; Glucuronides - metabolism; Health aspects; Humans; Models, Biological; Neoplasms - microbiology; Neoplasms - pathology; Neoplasms - therapy; original-article; Prodrugs; Prodrugs - metabolism; Prodrugs - therapeutic use; Tumors; Taiwan; prodrug-activating bacteria; b-glucuronidase; luminescence; non-invasive imaging; glucuronide prodrug; optical imaging
• ISSN: 0929-1903; 1476-5500
• DOI: 10.1038/cgt.2008.10

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. β-glucuronidase and the luxCDABE gene cluster were expressed in the DH5α strain of Escherichia coli to generate DH5α-lux/βG. 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 βG activity, we found that DH5α-lux/βG preferentially localized and replicated within CL1-5 human lung tumors in mice. The intensity of luminescence, CFU and βG activity increased with time, indicating bacterial replication occurred in tumors. In comparison with DH5α-lux/βG, 9AC or 9ACG treatment, combined systemic administration of DH5α-lux/βG 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.