Comparison of gene therapy with the herpes simplex virus thymidine kinase gene and the bacterial cytosine deaminase gene for the treatment of hepatocellular carcinoma.
BACKGROUND
Bystander effects induced by suicide gene/prodrug systems play an essential role in achieving successful antitumor effects. Although it has been shown in several in vitro studies that the bacterial cytosine deaminase (CD) gene/5-fluorocytosine (5-FC) system is superior to the herpes simplex virus thymidine kinase (HSV-TK) gene/ganciclovir (GCV) system, we examined here which suicide gene system was more promising in vivo for the treatment of hepatocellular carcinoma (HCC).


METHODS
BNL1ME A.7R.1 murine HCC cells were retrovirally transduced with the HSV-TK or CD gene, and bystander effects caused by the appropriate prodrug treatment were examined not only in vitro but also in vivo.


RESULTS
The CD/5-FC system was superior to the HSV-TK/GCV system in HCC cell elimination in vitro. The bystander effect of the HSV-TK/GCV was shown to be substantially dependent on cell-to-cell contact, whereas that of the CD/5-FC was not. However, antitumor effects on HCC and tumor immunity to parental HCC induced by the HSV-TK/GCV system were not inferior and even superior to those induced by the CD/5-FC system. Bystander effects induced by the suicide gene/prodrug systems in immunocompetent syngeneic mice were much more profound than those induced in vitro. However, significant bystander effects were not observed in athymic nude mice.


CONCLUSIONS
These results suggest that both HSV-TK/GCV and CD/5-FC systems are useful for the treatment of HCC. The results also suggest that T-cell-mediated immune responses elicited by the suicide gene/prodrug systems play a substantial role in antitumor effects in vivo.
Kuriyama
S
S
Third Dept. of Internal Medicine, Nara Medical University, Kashihara, Japan.
Mitoro
A
A
Yamazaki
M
M
Tsujinoue
H
H
Nakatani
T
T
Akahane
T
T
Toyokawa
Y
Y
Kojima
H
H
Okamoto
S
S
Fukui
H
H
D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use; D000998:Antiviral Agents / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000628:therapy*; D043525:Cytosine Deaminase; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics*; D005260:Female; D005437:Flucytosine / Q000627:therapeutic use; D015774:Ganciclovir / Q000627:therapeutic use; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D008113:Liver Neoplasms / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009700:Nucleoside Deaminases / Q000235:genetics*; D011355:Prodrugs / Q000627:therapeutic use; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics*; D018709:Statistics, Nonparametric; D013937:Thymidine Kinase / Q000235:genetics*; D014407:Tumor Cells, Cultured
D000935:Antifungal Agents; D000998:Antiviral Agents; D011355:Prodrugs; D005437:Flucytosine; D013937:Thymidine Kinase; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; D015774:Ganciclovir