Superiority of yeast over bacterial cytosine deaminase for enzyme/prodrug gene therapy in colon cancer xenografts.
The enzyme/prodrug strategy using bacterial cytosine deaminase (bCD) and 5-fluorocytosine (5-FC) is currently under investigation for cancer gene therapy. A major limitation for the use of bCD is that it is inefficient in the conversion of 5-FC into 5-fluorouracil. In the present study, we show that the K(m) of yeast cytosine deaminase (yCD) for 5-FC was 22-fold lower when compared with that of bCD. HT29 human colon cancer cells transduced with yCD (HT29/yCD) were significantly more sensitive to 5-FC in vitro than HT29 cells transduced with bCD (HT29/bCD). In tumor-bearing nude mice, complete tumor regression was observed in 6 of 13 HT29/yCD tumors in response to 5-FC treatment (500 mg/kg i.p. daily, 5 days a week for 2 weeks), whereas 0 of 10 HT29/bCD tumors were cured. Our study demonstrates an improved efficacy of the CD/5-FC treatment strategy when yCD was used. This enzyme has, therefore, a high potential to increase the therapeutic outcome of the enzyme/prodrug strategy in cancer patients.
Kievit
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E
Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor 48109-0582, USA.
Bershad
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E
Ng
E
E
Sethna
P
P
Dev
I
I
Lawrence
T S
TS
Rehemtulla
A
A
D000818:Animals; D001419:Bacteria / Q000201:enzymology*; D003110:Colonic Neoplasms / Q000628:therapy*; D043525:Cytosine Deaminase; D005260:Female; D005437:Flucytosine / Q000627:therapeutic use*; D005472:Fluorouracil / Q000494:pharmacology; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D009700:Nucleoside Deaminases / Q000235:genetics*; D011355:Prodrugs / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D015003:Yeasts / Q000201:enzymology*
D011355:Prodrugs; D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; D005472:Fluorouracil