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 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.
Cheng
C-M
CM
Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Lu
Y-L
YL
Chuang
K-H
KH
Hung
W-C
WC
Shiea
J
J
Su
Y-C
YC
Kao
C-H
CH
Chen
B-M
BM
Roffler
S
S
Cheng
T-L
TL
D000818:Animals; D001419:Bacteria / Q000235:genetics / Q000378:metabolism*; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000382:microbiology / Q000473:pathology / Q000628:therapy*; D011355:Prodrugs / Q000378:metabolism / Q000627:therapeutic use*
D020719:Glucuronides; D011355:Prodrugs; D005966:Glucuronidase