Specific targeting of cytosine deaminase to solid tumors by engineered Clostridium acetobutylicum.
The presence of severe hypoxia and necrosis in solid tumors offers the potential to apply an anaerobic bacterial enzyme/prodrug approach in cancer treatment. In this context the apathogenic C. acetobutylicum was genetically engineered to express and secrete E. coli cytosine deaminase (CDase). Considerable levels of functional cytosine deaminase were detected in lysates and supernatants of recombinant C acetobutylicum cultures. After administration of the recombinant Clostridium to rhabdomyosarcoma bearing rats used as a model, cytosine deaminase could be detected at the tumor site. Moreover, following administration of the vascular targeting agent combretastatin A-4 phosphate significantly increased levels of cytosine deaminase were detected at the tumor site as a consequence of enlarged tumor necrosis and subsequently improved growth of C. acetobutylicum. The results provide evidence for the potential application of Clostrisdium-based therapeutic protein transfer to tumors in anticancer therapy.
Theys
J
J
Laboratory of Bacteriology, Rega Institute for Medical Research, Leuven, Belgium.
Landuyt
W
W
Nuyts
S
S
Van Mellaert
L
L
van Oosterom
A
A
Lambin
P
P
Anné
J
J
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D003013:Clostridium / Q000201:enzymology / Q000235:genetics*; D043525:Cytosine Deaminase; D017931:DNA Primers / Q000737:chemistry; D016503:Drug Delivery Systems; D004926:Escherichia coli / Q000201:enzymology; D005437:Flucytosine / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D066298:In Vitro Techniques; D009368:Neoplasm Transplantation; D009700:Nucleoside Deaminases / Q000235:genetics* / Q000378:metabolism; D010957:Plasmids; D051381:Rats; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D012208:Rhabdomyosarcoma / Q000201:enzymology / Q000628:therapy*; D012878:Skin Neoplasms / Q000201:enzymology / Q000628:therapy*; D013267:Stilbenes / Q000494:pharmacology
D000935:Antifungal Agents; D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D017931:DNA Primers; D011994:Recombinant Proteins; D013267:Stilbenes; D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; C058728:fosbretabulin; D005472:Fluorouracil