RETROVIRAL DELIVERY OF DNA INTO THE LIVERS OF TRANSGENIC MICE BEARINGPREMALIGNANT AND MALIGNANT HEPATOCELLULAR CARCINOMAS

To develop gene therapy for hepatocellular carcinoma (HCC), we infused mice through the portal vein with retrovirus carrying the Escherichia coli beta-galactosidase reporter gene under the transcriptional contr ol of the viral long terminal repeat (LTR) and the promoter from the m ouse multidrug resistance gene mdrlb. Two transgenic mouse HCC models were used, one bearing the human hepatitis B viral envelope protein an d the other SV40 T antigen. These animals develop HCC with predictable pathological manifestations. The viral transduction efficiency appear ed to depend upon the stage of the disease in the animals. The most ef ficient transduction occurred when the livers had developed microscopi c nodular hyperplasia; in some cases as many as 0.01-0.1 copies/cell w ere transduced. The transduction efficiency was lower in the late stag e of the disease when livers had a heavy tumor burden and in the early stage when no lesion was evident. Low viral transduction efficacy was also seen in nontransgenic animals but was significantly increased by partial hepatectomy. The expression of the reporter gene in these ani mals was very low, as determined by histological staining. These resul ts suggest that hepatocarcinogenesis can enhance retroviral delivery o f foreign genes into the liver. Further development by increasing the viral transducing efficiency and the level of expression of transduced gene is required.