Enzyme/prodrug gene therapy for human colon cancer cells using adenovirus-mediated transfer of the Escherichia coli cytosine deaminase gene driven by a CAG promoter associated with 5-fluorocytosine administration.
Escherichia coli cytosine deaminase (CD), which is a prokaryotic enzyme, converts nontoxic prodrug 5-fluorocytosine (5-FC) into the toxic chemotherapeutic agent 5-fluorouracil (5-FU). To investigate an enzyme/prodrug gene therapy for colorectal cancer, using adenoviral gene transfer of the E. coli CD gene associated with administration of 5-FC, we constructed replication-defective adenovirus vectors expressing the E. coli CD gene or lacZ gene driven by a CAG promoter (composed of a cytomegalovirus immediate early enhancer and a chicken beta-actin promotor). The present study demonstrated that an adenoviral gene transfer system using a CAG promoter induced sufficient gene expression of CD to confer the cytotoxicity of 5-FC to HT29 human colon cancer cells by converting it into 5-FU even at an moi of one. Furthermore, experimental gene therapy using intratumoral injection of the CD-expressing adenovirus with systemical administration of 5'-FC successfully suppressed the growth of established HT29 subcutaneous tumors in nude mice. These results suggest that enzyme/prodrug gene therapy using the adenoviral gene transfer of the E. coli CD gene with concomitant administration of 5-FC may be an effective strategy in the local control of colorectal cancer.
Koyama
F
F
First Dept. of Surgery, Nara Medical University, Kashihara-city, Japan.
Sawada
H
H
Fujii
H
H
Hirao
T
T
Ueno
M
M
Hamada
H
H
Nakano
H
H
D000256:Adenoviridae; D000818:Animals; D003110:Colonic Neoplasms / Q000235:genetics* / Q000628:therapy*; D043525:Cytosine Deaminase; D004926:Escherichia coli / Q000235:genetics; D005437:Flucytosine / Q000627:therapeutic use*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D009700:Nucleoside Deaminases / Q000235:genetics* / Q000627:therapeutic use*; D011355:Prodrugs / Q000627:therapeutic use*; D011401:Promoter Regions, Genetic; D014407:Tumor Cells, Cultured
D011355:Prodrugs; D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase