Cancer Chemotherapy and Pharmacology

, Volume 32, Issue 4, pp 293–300 | Cite as

Cytotoxic properties of a new synthetic demethylpodophyllotoxin derivative, BN 58705, against human tumor cell lines

  • Hideki Morimoto
  • Paola Princine
  • Jean-Pierre Robin
  • Colette Broquet
  • Jean Michel Mencia-Huerta
  • Pierre Braquet
  • Benjamin Bonavida
Original Articles Demethylpodophyllotoxin, BN 58705, Cytotoxicity


The in vitro cytotoxic properties of a newly synthesized demethylpodophyllotoxin derivative, 4-o-butanoyl-4′-demethylpodophyllotoxin (BN 58705), were determined by using several human tumor cell lines of different histological origin and of different sensitivity to conventional chemotherapeutic drugs (Adriamycin andcis-diammine-dichloride platinum). BN 58705 is shown to be cytotoxic against various human tumor cell lines as assessed by the MTT assay. Furthermore, BN 58705 is shown to be cytotoxic against several drug-resistant tumor cell lines. BN 58705 is cytotoxic at concentrations 100- to 1000-fold lower than those of Adriamycin orcis-diammine-dichloride platinum required to achieve similar cytotoxicity. BN 58705 did not mediate DNA fragmentation of target cells, whereas the epipodophyllotoxin-like etoposide induced DNA cleavage by stabilizing the DNA-enzyme intermediate. Like vinca alkaloids, BN 58705 induced a block in the mitotic phase of the cell cycle. By comparison, BN 58705 exerted a stronger cytotoxic activity in vitro than did either etoposide, an epipodophyllotoxin, or vincristine, a vinca alkaloid. When BN 58705 was applied in vivo in mice, it resulted in low toxicity (50% lethal dose, 150 mg/kg). These results demonstrate than BN 58705 is cytotoxic to drug-resistant human tumor cell lines and is manyfold more potent than conventional drugs. The cytotoxic potency and low toxicity of BN 58705 are important criteria to establish its potential chemotherapeutic efficacy in vivo.


Etoposide Vincristine Adriamycin Human Tumor Cell Line Vinca Alkaloid 
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counts per minute

BN 58705



3-(4,5-dimethyl-thiazoyl-2-yl)-2,5-diphenyl-tetrazolium bromide


optical density


TRIS (hydroxymethyl) aminomethane


ethylenediaminetetraacetic acid




propidium iodide


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  1. 1.
    Bender RA, Hamel E, Hande KR (1990) Plant alkaloids. In: Chabner BA, Collins JM (eds) Cancer chemotherapy. J. B. Lippincott, New York, pp 253–275Google Scholar
  2. 2.
    Bosl G, Yagoda A, Golbey RB, Whitmore W Jr, Herr H, Sogani P, Morse M, Vogelzang N, MacDonald G (1985) Role of etoposide-based chemotherapy in the treatment of patients with refractory or relapsing germ cell tumors. Am J Med 78:423–428Google Scholar
  3. 3.
    Bryan J (1972) Definition of three classes of binding sites in isolated microtubule crystals. Biochemistry 11:2611–2616Google Scholar
  4. 4.
    Chang MP, Baldwin RL, Bruce C, Wisnieski BJ (1989) Second cytotoxic pathway of diphtheria toxin suggested by nuclease activity. Science 246:1165–1168Google Scholar
  5. 5.
    Duke RC, Chervenak R, Cohen JJ (1983) Endogenous endonuclease-induced DNA fragmentation: an early event in cell-mediated cytolysis. Proc Natl Acad Sci USA 80:6361–6365Google Scholar
  6. 6.
    Green LM, Redde JL, Ware CF (1984) Rapid coloremetric assay: application to the quantitation of cytotoxic and growth inhibitory lymphokines. J Immunol Methods 70:257–268Google Scholar
  7. 7.
    Johnson IS, Armstrong JG, Groman M, Burnett JP Jr (1963) The vinca alkaloids: a new class of oncolytic agents. Cancer Res 23: 1390–1427Google Scholar
  8. 8.
    Krishan A, Paika K, Frei E (1975) Cytofluorometric studies on the action of podophyllotoxins and epipodophyllotoxins (VM 26, VP 16213) on the cell cycle transverse of human lymphoblasts. J Cell Biol 66:521–530Google Scholar
  9. 9.
    Loike JD (1982) VP-16-213 and podophyllotoxin: a study on the relationship seen in chemical structure and biological activity. Cancer Chemother Pharmacol 7:103–111Google Scholar
  10. 10.
    Loike JD, Horwitz SB (1976) Effect of podophyllotoxin and VP-16 on microtubule assembly in vitro and nucleoside transport in HeLa cells. Biochemistry 15:5435–5442Google Scholar
  11. 11.
    Loike JD, Horwitz SB (1976) Effects of VP-16-213 on the intracellular degradation of DNA in HeLa cells. Biochemistry 15:5443–5448Google Scholar
  12. 12.
    Long BH, Musial ST, Brattain MG (1984) Comparison of cytotoxicity and DNA breakage activity of congeners of podophyllotoxin including VP-16-213 and VM-26: a quantitative structure activity relationship. Biochemistry 23:1183–1188Google Scholar
  13. 13.
    Louie KG, Hamilton TC, Winker MA, Behrens BC, Tsuruo T, Klecker RW Jr, Mckoy WM, Grotzinger KR, Myers CE, Young RC, Ozols RF (1986) Adriamycin accumulation and metabolism in Adriamycin-sensitive and-resistant human ovarian cancer cell lines. Biochem Pharmacol 35:467–472Google Scholar
  14. 14.
    Mattern J, Bak M, Hahn EW, Volur M (1988) Human tumor xenografts as model for drug testing. Cancer Metastasis Rev 7:263–284Google Scholar
  15. 15.
    Minocha A, Long B (1984) Inhibition of the DNA catenation activity of type II topoisomerase by VP-16-213 and VM-26. Biochem Biophys Res Commun 122:165–170Google Scholar
  16. 16.
    Morimoto H, Safrit J, Bonavida B (1991) Synergistic effect of tumor necrosis factor- and diphtheria toxin-mediated cytotoxicity in sensitive and resistant human ovarian tumor cell lines. J Immunol 147: 2609–2616Google Scholar
  17. 17.
    Nio Y, Zighelboim J, Berek J, Bonavida B (1990) Sensitivity of ovarian tumor cells to effector cells generated by various biological response modifiers. Nat Immun Cell Growth Regul 9:283–296Google Scholar
  18. 18.
    O'Dwyer PJ, Leyland-Jones B, Alonso MT, Marsoni S, Wittes RE (1985) Etoposide (VP-16-213): current status on an active anticancer drug. N Engl J Med 312:692–697Google Scholar
  19. 19.
    Pollack A, Moulis H, Block NL, Irvin GL III (1984) Quantitation of cell kinetic responses using simultaneous flow cytometric measurements of DNA and nuclear protein. Cytometry 5:473–481Google Scholar
  20. 20.
    Radice PA, Bunn PA, Ihde DC (1979) Therapeutic trials with VP-16-213 and VM-26: active agents in small cell lung cancer, non-Hodgkin's lymphomas and other malignancies. Cancer Treat Rep 63: 1231–1239Google Scholar
  21. 21.
    Rivera G, Dahl GV, Bowman WP, Avery TL, Wood A, Aur RJ (1980) VM26 and cytosine arabinoside combination chemotherapy for initial induction failures in childhood lymphocytic leukemia. Cancer 46:1727–1730Google Scholar
  22. 22.
    Ross W, Rowe T, Glisson B, Yalowich J, Liu L (1984) The role of topoisomerase II in mediating epipodophyllotoxin-induced cleavage. Cancer Res 44:5857–5860Google Scholar
  23. 23.
    Schmid DS, Tite JP, Ruddle NH (1986) DNA fragmentation: manifestation of target cell destruction mediated by cytotoxic T cells, lympphotoxin-secreting T cell clones and cell-free lymphotoxin-containing supernatant. Proc Natl Acad Sci USA 83:1881–1885Google Scholar
  24. 24.
    Vistica DT, Skehan P, Scudiero DA, Monks A, Pittman A, Boyd MR (1991) Tetrazolium-based assays for cellular viability: a critical examination of selected parameters affecting formazan production. Cancer Res 51:2515–2520Google Scholar
  25. 25.
    Wyllie AH (1980) Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284: 555–556Google Scholar
  26. 26.
    Yang L, Rowe TC, Lui LF (1985) Identification of DNA topoisomerase II as an intracellular target of anti tumor epipodophyllotoxins in simian virus 40-infected monkey cells. Cancer Res 45:5872–5876Google Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • Hideki Morimoto
    • 1
    • 2
  • Paola Princine
    • 3
  • Jean-Pierre Robin
    • 3
  • Colette Broquet
    • 3
  • Jean Michel Mencia-Huerta
    • 3
  • Pierre Braquet
    • 3
  • Benjamin Bonavida
    • 1
    • 2
  1. 1.Department of Microbiology and ImmunologyUniversity of California at Los Angeles, UCLA School of MedicineLos AngelesUSA
  2. 2.Jonsson Comprehensive Cancer CenterUniversity of California at Los Angeles, UCLA School of MedicineLos AngelesUSA
  3. 3.Institut Henri BeaufourLe Plessis-RobinsonFrance

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