Inhibition of rat hepatocellular carcinoma tumor growth after multiple infusions of recombinant Ad.AFPtk followed by ganciclovir treatment.
OBJECTIVE
The antitumor efficiency of thymidine kinase (tk) in Herpes Simplex virus-tk-based gene therapy of rat hepatocellular carcinoma (HCC) was examined by specific transcriptional targeting of tk to tumor cells by the alpha-fetoprotein (AFP) gene promoter and by multiple infusions of recombinant adenovirus Ad.AFPtk.


METHODS
We developed a surgical procedure that allows efficient, non-invasive delivery (during 2 months) of recombinant Ad via the intra-hepatic artery (IHA) route.


RESULTS
Treatment of tumor-bearing rats with either three or five doses of 5x10(9)pfu Ad.AFPtk, administered every 3 days, and followed by intra-peritoneal treatment with ganciclovir (GCV), resulted in tumor growth inhibition and apoptosis, when compared to untreated tumor-bearing rats or animals treated with Ad.AFPlacZ or buffered saline. No treatment-related toxicity was noted. Antitumor efficacy, based on tumor size and number of tumors, was demonstrated in more than 50% of Ad.AFPtk+GCV-treated rats, as compared to control rats (P<0.0005).


CONCLUSIONS
Our results demonstrate the safety and potential of multiple Ad.AFPtk administrations by the IHA route to inhibit HCC tumor growth, and support further clinical investigation of Ad.AFPtk gene therapy for treatment of multifocal tumor lesions in most primary liver cancers.
UMR 8532-CNRS, Gustave Roussy Institute, 39 rue Camille Desmoulins, 94805 Villejuif, France.
Antonio
A
Sa Cunha
Eric
E
Bonte
Sylvie
S
Dubois
Yves
Y
Chrétien
Tatyana
T
Eraiser
Claude
C
Degott
Christian
C
Bréchot
Phuong-Lan
PL
Tran
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000628:therapy*; D002455:Cell Division; D003131:Combined Modality Therapy; D015774:Ganciclovir / Q000494:pharmacology*; D015870:Gene Expression; D015316:Genetic Therapy; D006561:Herpes Simplex / Q000235:genetics; D008099:Liver / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000473:pathology / Q000628:therapy*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000633:toxicity; D013937:Thymidine Kinase / Q000235:genetics
D000998:Antiviral Agents; D011994:Recombinant Proteins; D013937:Thymidine Kinase; D015774:Ganciclovir