Retroviral delivery of DNA into the livers of transgenic mice bearing premalignant 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 control of the viral long terminal repeat (LTR) and the promoter from the mouse multidrug resistance gene mdr1b. Two transgenic mouse HCC models were used, one bearing the human hepatitis B viral envelope protein and the other SV40 T antigen. These animals develop HCC with predictable pathological manifestations. The viral transduction efficiency appeared to depend upon the stage of the disease in the animals. The most efficient transduction occurred when the livers had developed microscopic nodular hyperplasia; in some cases as many as 0.01-0.1 copies/cell were transduced. The transduction efficiency was lower in the late stage 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 animals was very low, as determined by histological staining. These results suggest that hepatocarcinogenesis can enhance retroviral delivery of foreign genes into the liver. Further development by increasing the viral transducing efficiency and the level of expression of transduced gene is required.
Kimura
O
O
Department of Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Yamaguchi
Y
Y
Gunning
K B
KB
Teeter
L D
LD
Husain
F
F
Kuo
M T
MT
D016475:3T3 Cells; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000818:Animals; D000952:Antigens, Polyomavirus Transforming; D001483:Base Sequence; D002460:Cell Line; D005786:Gene Expression Regulation; D006498:Hepatectomy; D006515:Hepatitis B virus; D006965:Hyperplasia; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011230:Precancerous Conditions / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D012091:Repetitive Sequences, Nucleic Acid; D014161:Transduction, Genetic; D014759:Viral Envelope Proteins; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000952:Antigens, Polyomavirus Transforming; D011993:Recombinant Fusion Proteins; D014759:Viral Envelope Proteins; D001616:beta-Galactosidase