Combined gene therapy with suicide gene and interleukin-12 is more efficient than therapy with one gene alone in a murine model of hepatocellular carcinoma.
OBJECTIVE
Gene therapy has emerged as a new form of treatment for unresectable hepatocellular carcinoma (HCC). We evaluate here the effect of IL-12 and the suicide gene thymidine kinase as single agents and in combination to treat experimental liver cancer.


METHODS
Recombinant adenoviruses expressing mouse interleukin-12 (AdCMVIL-12) or thymidine kinase of herpes simplex virus (AdCMVtk) or lacZ reporter gene (AdCMVlacZ) were constructed. The efficacy of the treatment was evaluated in a murine HCC model based on subcutaneous implantation of liver tumor cells (BNL).


RESULTS
Transduction of BNL cells after in vitro infection with AdCMVlacZ was very low at multiplicity of infection (moi) of 100, whereas 10-15% of cells were transduced when using moi 1,000. Similarly, production of IL-12 was detectable only in BNL cells infected with AdCMVIL-12 at moi 1,000. In vitro infection of BNL cells with AdCMVIL-12 at moi 100 did not abrogate tumorigenicity, whereas moi 1,000 resulted in inhibition of tumor growth in all mice as well as in abrogation of tumor formation in 3 out of 8 animals. In vivo studies showed that intratumor injection of AdCMVIL-12 induced a dose-dependent effect on tumor regression. However, none of the animals exhibited complete tumor elimination with this treatment. We observed that suppression of tumor growth was more intense in animals treated with the combination of AdCMVIL-12 plus AdCMVtk than in animals which received AdCMVtk or AdCMVIL-12 alone. The combined treatment resulted in a significant increase in animal survival, and 25% of treated animals were free of tumor for over 100 days without recurrence of the disease.


CONCLUSIONS
Combination of AdCMVIL-12 and AdCMVtk is more efficient than either of the two vectors alone for the treatment of the murine model of HCC used in this study.
Drozdzik
M
M
Department of Medicine, School of Medicine and Clinica Universitaria, University of Navarra, Pamplona, Spain.
Qian
C
C
Xie
X
X
Peng
D
D
Bilbao
R
R
Mazzolini
G
G
Prieto
J
J
D000256:Adenoviridae / Q000235:genetics; D000257:Adenoviridae Infections / Q000378:metabolism; D000818:Animals; D015197:Carcinogenicity Tests; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics*; D008114:Liver Neoplasms, Experimental / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011995:Recombination, Genetic; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics*; D014407:Tumor Cells, Cultured / Q000502:physiology
D018664:Interleukin-12; D013937:Thymidine Kinase