Inhibition of rat hepatocellular carcinoma tumor growth after multiple infusions of recombinant Ad.AFP tk followed by ganciclovir treatment

Abstract

Background/Aims: 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 α-fetoprotein (AFP) gene promoter and by multiple infusions of recombinant adenovirus Ad.AFP tk. 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 5×10 9 pfu Ad.AFP tk, 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.AFP lacZ 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.AFP tk+GCV-treated rats, as compared to control rats ( P<0.0005). Conclusions: Our results demonstrate the safety and potential of multiple Ad.AFP tk administrations by the IHA route to inhibit HCC tumor growth, and support further clinical investigation of Ad.AFP tk gene therapy for treatment of multifocal tumor lesions in most primary liver cancers.