Abstract
Adriamycin-oxidized dextran (ADM-OXD), a newly developed antineoplastic macromolecule, has demonstrated greater antitumor action in tumor-bearing animals than ADM. However, excess dosing of ADM-OXD readily induces specific hepatotoxicity in vivo. In this study, the toxicity of ADM-OXD to cultured hepatocytes and Kupffer cells was compared with that of ADM.
With primary cultured hepatocytes, the results obtained were completely opposite to those obtained previously in vivo. Judging from the activity of leaked hepatic enzyme and cell viability measured by MTT assay, ADM-OXD had no toxic action toward hepatocytes. ADM, on the other hand, showed severe toxicity. Morphological observation agreed with the results of biological monitoring. Cell desquamation and increased cell necrosis induced by addition of ADM were not observed after addition of ADM-OXD to the medium. With primary cultured Kupffer cells, ADM-OXD did show toxicity, but to a lesser degree than ADM. Particularly as measured by neutral red (NR) assay, which evaluates lysosomal function through NR uptake capacity, ADM-OXD as well as ADM showed severe toxicity toward Kupffer cells. Toxicity of ADM-OXD to hepatocytes, however, was induced only when hepatocytes were co-cultured with Kupffer cells. From these results it was concluded that the presence of Kupffer cells is necessary for the appearance of ADM-OXD-induced toxicity in hepatocytes. It seems likely that ADM-OXD is incorporated not into hepatocytes but into Kupffer cells, and that ADM dissociated in Kupffer cells transfers into hepatocytes, where it eventually exhibits toxic action.
