title: Delivery and cytotoxicity of RS-1541 in St-4 human gastric cancer cells in vitro by the low-density-lipoprotein pathway.
abstract: RS-1541 is a 13-O-palmitoyl derivative of rhizoxin, an inhibitor of tubulin 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 human 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 with higher LDL-receptor activities than in control cells. Excess amounts of LDL or 1 microM of monensin, a proton ionophore, significantly inhibited 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-1541 showed very low cellular uptake and cytotoxicity, irrespective of the LDL-receptor activities of these cells. These results demonstrate that the RS-1541/LDL complex is incorporated into the cells via the LDL receptor and that it manifests its cytotoxic activity after forming rhizoxin, the original antitumor agent, in the lysosomes.
authors.affiliation: Analytical and Metabolic Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Tokui
authors.forename: T
authors.initials: T
authors.lastname: Takatori
authors.forename: N
authors.initials: N
authors.lastname: Shinozaki
authors.forename: M
authors.initials: M
authors.lastname: Ishigami
authors.forename: A
authors.initials: A
authors.lastname: Shiraishi
authors.forename: T
authors.initials: T
authors.lastname: Ikeda
authors.forename: T
authors.initials: T
authors.lastname: Tsuruo
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000378:metabolism / Q000633:toxicity*; D002738:Chloroquine / Q000494:pharmacology; D004337:Drug Carriers; D004347:Drug Interactions; D006801:Humans; D007783:Lactones / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity; D008077:Lipoproteins, LDL / Q000378:metabolism; D008985:Monensin / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000188:drug therapy*; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D007783:Lactones; D008077:Lipoproteins, LDL; C087843:palmitoyl rhizoxin; D002738:Chloroquine; D008985:Monensin