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

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 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 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Bilheimer DW, Eisenberg S, Levy RI (1972) The metabolism of very low density lipoproteins. I. Preliminary in vitro and in vivo observations. Biochim Biophys Acta 260:212Google Scholar
  2. 2.
    Blomhoff R, Drevon CA, Eskild W, Helgerud P, Norum KR, Berg T (1984) Clearance of acetyl low density lipoprotein by rat liver endothelial cells. J Biol Chem 259:8898Google Scholar
  3. 3.
    Brown MS, Dana SE, Goldstein JL (1975) Receptor-dependent hydrolysis of cholesterol esters contained in plasma low density lipoprotein. Proc Natl Acad Sci USA 72:2925Google Scholar
  4. 4.
    Burstein M, Scholnick HR (1973) Lipoprotein-polyanion-metal interaction. Adv Lipid Res 11:67Google Scholar
  5. 5.
    Filipowska D, Filipowski T, Morelowska B, Kazanowska W, Laudanski T, Lapinjoki S, Åkerlund M, Breeze A (1992) Treatment of cancer patients with a low-density-lipoprotein delivery vehicle containing a cytotoxic drug. Cancer Chemother Pharmacol 29:396Google Scholar
  6. 6.
    Gal D, Ohashi M, MacDonald PC, Buchsbaum HJ, Simpson ER (1981) Low-density lipoprotein as a potential vehicle for chemotherapeutic agents and radionucleotides in the management of gynecologic neoplasms. Am J Obstet Gynecol 139:877Google Scholar
  7. 7.
    Goldstein JL, Brown MS (1974) Binding and degradation of low density lipoproteins by cultured human fibroblasts. J Biol Chem 249:5153Google Scholar
  8. 8.
    Goldstein JL, Brown SB (1977) The low-density lipoprotein pathway and its relation to atherosclerosis. Annu Rev Biochem 46:897Google Scholar
  9. 9.
    Havel RJ, Eder MA, Bradgon SM (1955) The distribution and chemical composition of ultracentrifugally separated lipoproteins. J Clin Invest 34:1345Google Scholar
  10. 10.
    Iwasaki S, Kobayashi H, Furukawa J, Namikoshi M, Okuda S, Sato Z, Matsuda I, Noda T (1984) Studies on macrocyclic lactone antibiotics. VII. Structure of a phytotoxin rhizoxin produced byRhizopus chinensis. J Antibiot 37:354Google Scholar
  11. 11.
    Kerr DJ, Bisset D, Graham M, Setanoians A, Chadwick G, Cassidy J, Henrar R, Kaye SB (1992) A phase I and pharmacokinetic study of rhizoxin (abstract). Proceedings, 7th NCI-EORTC Symposium on New Drugs in Cancer Therapy, Amsterdam, March 17–20, p 120Google Scholar
  12. 12.
    Kobayashi T, Sasagawa K, Hirai K, Nishimura T, Tsuruo T, Iwasaki S, Tsukagoshi S, Okuda S (1989) Antitumor activity of new antitumor antibiotic derivatives, acylated rhizoxins. Proceedings, 16th International Congress of Chemotherapy, Jerusalem, June 11–16, p 739Google Scholar
  13. 13.
    Lombardi P, Norata G, Maggi FM, Canti G, Franco P, Nicolin A, Catapano AL (1989) Assimilation of LDL by experimental tumours in mice. Biochim Biophys Acta 1003:301Google Scholar
  14. 14.
    Lowry OH, Rosenbrough NJ, Farr AL, Randall RJ (1951) Protein measurment with the Folin phenol regent. J Biol Chem 93:265Google Scholar
  15. 15.
    Lundberg B (1992) Assembly of prednimustine low-density-lipoprotein complexes and their cytotoxic activity in tissue culture. Cancer Chemother Pharmacol 29:241Google Scholar
  16. 16.
    Noda T, Hashiba T, Sato Z (1980) The structural changes in young swollen roots of rice seedlings infected withRhizopus chinensis Saito. Ann Phytopathol Soc Jpn 46:40Google Scholar
  17. 17.
    Norata G, Canti G, Ricci L, Nicolin A, Trezzi E, Catapano AL (1984) In vivo assimilation of low density lipoproteins by a fibrosarcoma tumour line in mice. Cancer Lett 25:203Google Scholar
  18. 18.
    Peterson CO, Masquelier M, Rudling M, Söderberg-Reid K, Vitols S (1991) Lipoproteins, malignancy, and anticancer agents. In: Shaw JM (ed) Lipoproteins as carriers of pharmacological agents. Marcel Dekker, New York, p 175Google Scholar
  19. 19.
    Samadi-Baboli M, Favre G, Bernadou J, Berg D, Soula G (1990) Comparative study of the incorporation of ellipticine-esters into low density lipoprotein (LDL) and selective cell uptake of drug-LDL complex via the LDL receptor pathway in vitro. Biochem Pharmacol 40:203Google Scholar
  20. 20.
    Samadi-Baboli M, Favre G, Canal P, Soula G (1993) Low density lipoprotein for cytotoxic drug targeting: improved activity of an elliptinium derivative against B-16 melanoma in mice. Br J Cancer 68:319Google Scholar
  21. 21.
    Takahashi M, Iwasaki S, Kobayashi H, Okuda S (1987) Studies on macrocyclic lactone antibiotics. XI. Anti-mitotic and anti-tubulin activity of new antitumor antibiotics, rhizoxin and its homologues. J Antibiotics 40:66Google Scholar
  22. 22.
    Takahashi M, Iwasaki S, Kobayashi H, Okuda S, Murai T, Sato Y (1987) Rhizoxin binding to tubulin at the maytansine-binding site. Biochim Biophys Acta 926:215Google Scholar
  23. 23.
    Takatori T, Koizumi T, Tokui T, Shiraishi A, Tsuruo T (1994) Intracellular activation and cytotoxic action of RS-1541 (palmitoyl-rhizoxin) against cultured human tumor cells. Cancer Chemother Pharmacol 35:283Google Scholar
  24. 24.
    Tokui T, Kuroiwa C, Tokui Y, Sasagawa K, Kawai K, Kobayashi T, Ikeda T, Komai T (1994) Targeting of an antitumor agent, RS-1541 (palmitoyl-rhizoxin) via low-density lipoprotein receptor. Biopharm Drug Dispos 15:93Google Scholar
  25. 25.
    Tokui T, Tokui Y, Ishigami M, Tanzawa K, Ikeda T, Komai T (1994) Contribution of serum lipoproteins as carriers of antitumor agent: RS-1541 (palmitoyl-rhizoxin) in mice. Int J Pharm 110:277Google Scholar
  26. 26.
    Tsuruo T, Oh-hara T, Iida H, Tsukagoshi S, Sato Z, Matsuda I, Iwasaki S, Okuda S, Shimizu F, Sasagawa K, Fukami M, Fukuda K, Arakawa M (1986) Rhizoxin, a macrocyclic lactone antibiotic, as a new agent against human and murine tumor cells and their vincristine-resistant sublines. Cancer Res 46:381Google Scholar
  27. 27.
    Vitols S, Söderberg-Reid K, Masquelier M, Sjöström B, Peterson CO (1990) Low density lipoprotein for delivery of a water-insoluble alkylating agent to malignant cells. In vitro and in vivo studies of a drug-lipoprotein complex. Br J Cancer 62:724Google Scholar
  28. 28.
    Vitols S, Peterson C, Larsson O, Holm P, Åberg B (1992) Elevated uptake of low density lipoproteins by human lung cancer tissue in vivo. Cancer Res 52:6244Google Scholar

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

Personalised recommendations