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

Abstract

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.

Keywords

Etoposide Vincristine Adriamycin Human Tumor Cell Line Vinca Alkaloid 

Abbreviations

cpm

counts per minute

BN 58705

4-o-butanoyl-4′-demethylpodophyllotoxin

MTT

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

OD

optical density

TRIS

TRIS (hydroxymethyl) aminomethane

EDTA

ethylenediaminetetraacetic acid

FITC

fluoresceinisothiocyanate

PI

propidium iodide

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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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