DELIVERY AND CYTOTOXICITY OF RS-1541 IN ST-4 HUMAN GASTRIC-CANCER CELLS IN-VITRO BY THE LOW-DENSITY-LIPOPROTEIN PATHWAY

RS-1541 is a 13-O-palmitoyl derivative of rhizoxin, an inhibitor of tu bulin polymerization. RS-1541 has been shown to bind preferentially to plasma lipoproteins and to exhibit selective and sustained uptake by tumors in mice. To elucidate a mechanism of RS-1541 cytotoxicity, the cellular uptake and the cytotoxicity of a complex of RS-1541 with huma n low-density lipoprotein (RS-1541/ LDL complex) were investigated in cultured St-4 human gastric cancer cells. Both the cellular uptake and the cytotoxicity of the RS-1541/LDL complex were greater in cells wit h higher LDL-receptor activities than in control cells. Excess amounts of LDL or 1 mu M of monensin, a proton ionophore, significantly inhib ited both the uptake and the cytotoxicity of the complex. Chloroquine, an inhibitor of lysosomal enzymes, decreased the intracellular level of rhizoxin liberated from RS-1541 and suppressed the cytotoxicity of the RS-1541/LDL complex. However, a detergent-aided solution of RS-154 1 showed very low cellular uptake and cytotoxicity, irrespective of th e LDL-receptor activities of these cells. These results demonstrate th at the RS-1541/LDL complex is incorporated into the cells via the LDL receptor and that it manifests its cytotoxic activity after forming rh izoxin, the original antitumor agent, in the lysosomes.