Anticancer efficacy of systemically delivered anaerobic bacteria as gene therapy vectors targeting tumor hypoxia/necrosis.
A major obstacle in cancer gene therapy is selective tumor delivery. Previous studies have suggested that genetically engineered anaerobes of the genus Clostridium might be gene therapy vectors because of their ability to proliferate selectively in the hypoxic/necrotic regions common to solid tumors. However, the tumor colonization efficiency of the strain previously used was insufficient to produce any antitumor effect. Here we describe for the first time the successful transformation of C. sporogenes, a clostridial strain with the highest reported tumor colonization efficiency, with the E. coli cytosine deaminase (CD) gene and show that systemically injected spores of these bacteria express CD only in the tumor. This enzyme can convert the nontoxic prodrug 5-fluorocytosine (5-FC) to the anticancer drug 5-fluorouracil (5-FU). Furthermore, systemic delivery of 5-FC into mice previously injected with CD-transformed spores of C. sporogenes produced greater antitumor effect than maximally tolerated doses of 5-FU. Since most human solid tumors have hypoxic and necrotic areas this vector system has considerable promise for tumor-selective gene therapy.
Liu
S C
SC
Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305-5152, USA.
Minton
N P
NP
Giaccia
A J
AJ
Brown
J M
JM
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000628:therapy*; D015687:Cell Hypoxia; D003013:Clostridium / Q000201:enzymology / Q000235:genetics*; D043525:Cytosine Deaminase; D005437:Flucytosine / Q000627:therapeutic use; D005472:Fluorouracil / Q000627:therapeutic use; D018390:Gene Targeting / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000627:therapeutic use*; D051379:Mice; D008809:Mice, Inbred C3H; D009336:Necrosis; D009368:Neoplasm Transplantation; D009700:Nucleoside Deaminases / Q000235:genetics / Q000378:metabolism; D011355:Prodrugs / Q000627:therapeutic use
D011355:Prodrugs; D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; D005472:Fluorouracil