Preclinical and therapeutic utility of HVJ liposomes as a gene transfer vector for hepatocellular carcinoma using herpes simplex virus thymidine kinase

Abstract

Although gene therapy has been suggested to be a novel strategy to treat hepatocellular carcinoma ( HCC ) , no study showing the clinical feasibility of vectors to treat HCC has been reported. In this preclinical study, we show evidence indicating that hemagglutinating virus of Japan ( HVJ ) liposomes are a feasible vector to treat HCC in a clinical setting using ganciclovir ( GCV ) and herpes simplex virus thymidine kinase ( HSV -tk ) , which is driven by the cytomegalovirus immediate early enhancer / promoter ( plasmid pcDNA3 / HSV -tk ) . In in vitro experiments, almost complete tumor cell regression was achieved with the optimal GCV concentration ( 100 g / mL ) and more than 1 / 3 regression was seen even with a 20% transduction ratio using HuH7 HCC cells stably transformed by HSV -tk. HVJ liposomes showed a 19.7% ( mean ) transduction rate of the lacZ gene in a relatively large mass of more than 300 mm 3 in vivo, which is a clinically detectable size, implanted into SCID mice. Moreover, a single HSV -tk injection of HVJ liposomes followed by GCV treatment inhibited tumor growth at least within a week, and repeat administration was more effective. Furthermore, subcutaneous injection of an HVJ liposomes vehicle induced no apparent inflammatory response in C3H / HeN mice, whereas lacZ gene transfection resulted in inflammatory pathology, suggesting a lower immunogenicity of the HVJ envelope protein than those of bacteria -derived plasmid DNA or the -galactosidase gene product. From these findings, we conclude that HVJ liposomes are a clinically safe and effective gene transfer vector to treat HCC. Cancer Gene Therapy ( 2001 ) 8, 252 ± 258

Peptide-Based Nanoparticles for αvβ3 Integrin-Targeted DNA Delivery to Cancer and Uterine Leiomyoma Cells

“…Suicide gene therapy based on HSV-TK transgene and GCV metabolism specificities is widely used to selectively kill tumor cells [ 51 ]. To assess the potential use of the peptide DNA delivery vehicles studied here, we transferred HSV-TK genes into primary uterine leiomyoma cells obtained after myomectomy from women with the disease [ 52 ].…”

The application of antitumor drug-targeting models on liver cancer

“…Nude mice models are typically divided into subcutaneous transplantation model and orthotopic transplantation model. Hasegawa et al (2001) and Hirano et al (2001) adjusted the concentration of HuH7 (human hepatocellular carcinoma) to 5 Â 10 6 /mL and subcutaneously injected it into male SCID mice, and 3 weeks later, consecutively injected mice with HVJ liposomes for 5 days (Figure 2). As a consequence, HVJ liposomes acted pretty solid improvement on the body weight and pathological indicators of nude mice.…”

The newly established human hepatocyte cell line: application for the bioartificial liver

“…The plasmid including HSV-tk gene which Dr Hasegawa [32] provided was transfected to HepG2 by lipofection (Invitrogen Co., CA, USA), following selection with G418 (800 mg/ml) for 2 weeks. Each of colonies was checked for HSV/tk expression using RT-PCR and specific cytotoxity to GCV.…”