SPECIFIC TARGETING OF ADRIAMYCIN CONJUGATES WITH MONOCLONAL-ANTIBODIES TO HEPATOMA ASSOCIATED ANTIGENS TO INTRAHEPATIC TUMORS IN ATHYMIC MICE

Doxorubicin (adriamycin), once considered the treatment of choice for hepatocellular carcinoma (HCC), is known to cause cardiotoxicity and m yelotoxicity. To reduce the systemic toxicity of adriamycin by direct delivery of the drug to the tumor site, we established a panel of mono clonal antibodies (MAbs) to hepatoma associated antigens that were con jugated to adriamycin by a dextran bridge, Initially. the efficacy of these conjugates in suppressing tumor growth was assessed using a mode l of subcutaneous HCC tumors injected in athymic mice. In the second s tage of the study, we tested these conjugates in an experimental model in which human HCC was transplanted intrahepatically by intrasplenic injection, thus providing the tumor cells with growth factors and an a dequate cellular matrix, similar to the natural microenvironment of HC C. Anti-tumoral therapy resulted in lower serum alpha-fetoprotein (AFP ) levels in two of three experimental groups treated with different sp ecific conjugates as compared with control mice treated with the indiv idual components. Efficacy of targeting was enhanced using the intrahe patic model system for propagation of HCC and was demonstrated by fluo rescence of adriamycin and MAb in tumor tissue and absence of this flu orescence in healthy liver tissue surrounding the tumor. Reduction of systemic toxicity was shown by the absence of adriamycin fluorescence in myocardial tissue in conjugate-treated mice, whereas in all other t reatment groups, including mice treated with a mixture of adriamycin a nd specific MAb, there was strong myocardial fluorescence of adriamyci n.