We propose to extend our previous preliminary in vitro targeting studies to in vivo models to develop a new receptor-mediated approach to chemotherapy of hepatocellular carcinoma. The concept is based on the use of hepatotoxins, to destroy malignant cells, in combination with specific targeted-antagonists to achieve exclusive rescue of normal hepatocytes. This targeting is dependent on the ability of normal hepatocytes, and the inability of the majority of hepatocellular carcinomas to take up and degrade, intracellularly, galactose-terminal (asialo-) glycoproteins by a specific receptor-mediated endocytosis. Linkage of an appropriate antagonist to such glycoproteins could result in specific binding and release of antagonist with subsequent rescue of only normal, differentiated hepatocytes. We also propose to investigate new strategies to enhance the effectiveness of targeted rescue: 1) increased delivery of rescue agents to normal hepatocytes using asialoglycoprotein-polylysine carrier molecules to increase the amount of antagonists capable of being coupled to the carrier molecule 2) increased efficiency of antagonist release by the interposition of labile linkages. We will use two animal models to test these approaches: 1) inbred Buffalo rats implanted with a rat hepatoma cell line 2) rats bearing carcinogen-induced hepatomas. We will use serological and pathological measurements to determine the feasibility of the use of targeted rescue as an effective modality for the treatment of hepatocellular carcinoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA046801-01
Application #
3190212
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1988-02-01
Project End
1991-01-31
Budget Start
1988-02-01
Budget End
1989-01-31
Support Year
1
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Type
Schools of Medicine
DUNS #
City
Farmington
State
CT
Country
United States
Zip Code
06030
Liang, T J; Makdisi, W J; Sun, S et al. (1993) Targeted transfection and expression of hepatitis B viral DNA in human hepatoma cells. J Clin Invest 91:1241-6
Makdisi, W J; Wu, C H; Wu, G Y (1992) Methods of gene transfer into hepatocytes: progress toward gene therapy. Prog Liver Dis 10:1-24
Versland, M R; Wu, C H; Wu, G Y (1992) Strategies for gene therapy in the liver. Semin Liver Dis 12:332-9
Neda, H; Wu, C H; Wu, G Y (1991) Chemical modification of an ecotropic murine leukemia virus results in redirection of its target cell specificity. J Biol Chem 266:14143-6
Wu, G Y; Wu, C H (1991) Targeted delivery and expression of foreign genes in hepatocytes. Targeted Diagn Ther 4:127-49
Keegan-Rogers, V; Wu, C H; Wu, G Y (1991) Receptor-mediated protection of normal hepatocytes during chemotherapy for hepatocellular carcinoma. Targeted Diagn Ther 4:105-25
Wu, G Y; Wu, C H (1991) Delivery systems for gene therapy. Biotherapy 3:87-95
Wu, G Y; Wilson, J M; Shalaby, F et al. (1991) Receptor-mediated gene delivery in vivo. Partial correction of genetic analbuminemia in Nagase rats. J Biol Chem 266:14338-42
Keegan-Rogers, V; Wu, G Y (1990) Targeted protection of hepatocytes from galactosamine toxicity in vivo. Cancer Chemother Pharmacol 26:93-6
Wu, C H; Wilson, J M; Wu, G Y (1989) Targeting genes: delivery and persistent expression of a foreign gene driven by mammalian regulatory elements in vivo. J Biol Chem 264:16985-7

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