Cancer Chemotherapy and Pharmacology

, Volume 36, Issue 1, pp 1–6 | Cite as

Delivery and cytotoxicity of RS-1541 in St-4 human gastric cancer cells in vitro by the low-density-lipoprotein pathway

  • Taro Tokui
  • Toshiro Takatori
  • Nobue Shinozaki
  • Michi Ishigami
  • Akio Shiraishi
  • Toshihiko Ikeda
  • Takashi Tsuruo
Original Article RS-1541, Low-Density Lipoprotein, Targeting


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 μM 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.

Key words

RS-1541 Low-density lipoprotein Targeting 


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Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • Taro Tokui
    • 1
  • Toshiro Takatori
    • 2
  • Nobue Shinozaki
    • 1
  • Michi Ishigami
    • 1
  • Akio Shiraishi
    • 2
  • Toshihiko Ikeda
    • 1
  • Takashi Tsuruo
    • 3
  1. 1.Analytical and Metabolic Research LaboratoriesSankyo Co., Ltd.TokyoJapan
  2. 2.Biological Research LaboratoriesSankyo Co., Ltd.TokyoJapan
  3. 3.Institute of Molecular and Cellular BiosciencesUniversity of TokyoTokyoJapan

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