Targeted therapy for hepatic cancer: Good in theory, problematic in practice

Abstract

We present evidence that normal hepatocytes can be specifically protected from galactosamine toxicity in vitro by targeting an antagonist to these cells via receptor‐mediated endocytosis. The strategy is based upon the following principles: 1) galactosamine is a highly selective hepatotoxin that causes a dose‐dependent depletion of uridine intermediates; 2) galactosamine toxicity can be antagonized by supplemental administration of uridine; 3) normal hepatocytes possess unique cell‐surface receptors that can internalize galactose terminal (asialo‐) glycoproteins with subsequent degradation of the glycoprotein ligand. Based on these facts, we hypothesized that chemical coupling of a galactosamine antagonist to an asialoglycoprotein could result in cell‐specific delivery and protection of normal hepatocytes by targeting the antagonist via asialoglycoprotein receptors. Using a model system consisting of freshly isolated rat hepatocytes (receptor(+)) and Morris 7777 rat hepatoma (receptor (−)) cells, sensitivity to galactosamine in vitro was determined and found to be similar for both types of cells. A targetable antagonist was synthesized by coupling uridine monophosphate to asialoorosomucoid in a molar ratio of 5 to 1. Exposure of Morris 7777 cells to the targetable antagonist in the presence of a toxic concentration of galactosamine did not protect these cells as evidenced by a steady decline in the number of viable cells in a fashion identical to cells treated with galactosamine alone. However, normal hepatocytes that received the conjugate in the presence of galactosamine were protected as their viable cell number remained the same as control (untreated) cells. Competition by an excess of asialoglycoprotein inhibited the protective effect of the conjugate, supporting the concept that the asialoglycoprotein component of the conjugate was responsible for the specific delivery of the antagonist to the target cells.

Drug Targeting with Glycoproteins and Other Peptide Carriers: An Overview

“…Asialoglycoproteins were linked to bacterial toxins yielding extremely potent drugs that inhibit protein synthesis in the hepatoma cells at a concentration of lO·I1M (Cawley et aI, 1981;Chang and Kullberg, 1982;Simpson et ai, 1982). Since in some but not all hepatomas the density of the particular receptor is considerably decreased, this approach is apt to failure in such cases (Wright, 1989). This receptor heterogeneity can be used to rescue non-cancer cells from the toxication of high doses of methotrexate .…”