DESCRIPTION: (Applicant's Description) The development of a ligand-directed, liver-specific, 5-flurouracil containing neoglycoconjugate is proposed for the treatment of hepatocellular carcinoma. This neoglycoconjugate is comprised of the liver-specific ligand YEE(ahGalNac)3 covalently linked to a 5FU pro-drug via a small molecular weight linker. The resultant construct is homogeneous, defined, chemically biodegradable and capable of specifically delivering it's drug payload via receptor-mediated endocytosis. Preliminary studies have shown that the neoglycoconjugate is taken up specifically and at an enhanced rate by hepatocytes resulting in increased bioeffectiveness. In vivo biodistribution experiments revealed the neoglycoconjugate is delivered rapidly and specifically to the liver of mice. The object of the proposed studies is to demonstrate the feasibility of the liver specific neogycoconjugate as an effective chemotherapeutic treatment. To accomplish this end, initially a range of concentrations will be determined by intravenous injection into mice. Subsequently, tumor pharmacokinetics, and bioeffectiveness will be determined by intravenous injection into immunodeficient mice bearing HCC xenografts. These studies are designed to satisfy FDA regulations concerning non-clinical testing of therapeutic drugs. Phase I will be extended to consider the commercial scale production of the neoglycoconjugate and toxicity testing in larger animals in Phase II. These studies will subsequently be extended to Phase I clinical trials. PROPOSED COMMERCIAL APPLICATION: Hepatocellular carcinoma (HCC) is untreatable. Infections with hepatitis virus and cirrhosis are major risk factors for liver cancer. HCC is a major health problem worldwide with 0.5-1 million deaths per year. In 1998, 13,900 deaths in the U.S. were related to liver cancer and in other areas, such as China and Southeast Asia, as many as 50% of all cancers are attributed to liver cancer. Potentially any drug may be inserted within the liverspecific ligand-linker-prodrug construct. A virtually untapped market is available for new drug treatment regimens.