Tumor-targeting prodrug-activating bacteria for cancer therapy

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 DH5 alpha strain of Escherichia coli to generate DH5 alpha-lux/beta G. These bacteria emitted light for imaging and hydrolyzed the glucuronide prodrug 9ACG to the topoisomerase 1 inhibitor 9-aminocamptothecin ( 9AC). By optical imaging, colony-forming units ( CFUs) and staining for beta G activity, we found that DH5 alpha-lux/beta G preferentially localized and replicated within CL1-5 human lung tumors in mice. The intensity of luminescence, CFU and beta G activity increased with time, indicating bacterial replication occurred in tumors. In comparison with DH5 alpha-lux/beta G, 9AC or 9ACG treatment, combined systemic administration of DH5 alpha-lux/beta G 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.