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Molecular Pharmacology

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Research ArticleArticle

Mechanism of Mitotic Block and Inhibition of Cell Proliferation by the Semisynthetic Vinca Alkaloids Vinorelbine and Its Newer Derivative Vinflunine

Vivian K. Ngan, Krista Bellman, Bridget T. Hill, Leslie Wilson and Mary Ann Jordan
Molecular Pharmacology July 2001, 60 (1) 225-232; DOI: https://doi.org/10.1124/mol.60.1.225
Vivian K. Ngan
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Krista Bellman
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Bridget T. Hill
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Leslie Wilson
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Mary Ann Jordan
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Abstract

The two second-generation Vinca alkaloids, vinorelbine and vinflunine, affect microtubule dynamics very differently from vinblastine, a first generation Vinca alkaloid. For example, vinblastine strongly suppresses the rate and extent of microtubule shortening in vitro, whereas vinorelbine and vinflunine suppress the rate and extent of microtubule growing events. We asked whether these differences result in differences in mitotic spindle organization that might be responsible for the superior antitumor activities of the two second-generation Vinca alkaloids. IC50 values for inhibition of HeLa cell proliferation for vinflunine, vinorelbine, and vinblastine were 18, 1.25, and 0.45 nM, respectively, similar to the concentrations that induced mitotic block at the metaphase/anaphase transition (38, 3.8, and 1.1 nM, respectively), indicating that mitotic block is a major contributor to antiproliferative action for all three drugs. Mitotically blocked cells exhibited aberrant spindles, consistent with induction of block by suppression of microtubule dynamics. Despite differences in their actions on individual dynamic instability parameters, morphologically detectable differences in spindle effects among the three drugs were minimal, indicating that overall suppression of dynamics may be more important in blocking mitosis than specific effects on growth or shortening. We also found that the peak intracellular drug concentration at the mitotic IC50 value was highest for vinflunine (4.2 ± 0.2 μM), intermediate for vinorelbine (1.3 ± 0.1 μM), and more than 10-fold lower for vinblastine (130 ± 7 nM), suggesting that intracellular binding reservoir(s) may be partially responsible for vinflunine's high efficacy and minimal side effects.

  • Abbreviations

    PIPES
    piperazine-N,N′-bis(2-ethanesulfonic acid)
    • Received February 5, 2001.
    • Accepted April 16, 2001.
    • The American Society for Pharmacology and Experimental Therapeutics
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    Molecular Pharmacology: 60 (1)
    Molecular Pharmacology
    Vol. 60, Issue 1
    1 Jul 2001
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    Research ArticleArticle

    Mechanism of Mitotic Block and Inhibition of Cell Proliferation by the Semisynthetic Vinca Alkaloids Vinorelbine and Its Newer Derivative Vinflunine

    Vivian K. Ngan, Krista Bellman, Bridget T. Hill, Leslie Wilson and Mary Ann Jordan
    Molecular Pharmacology July 1, 2001, 60 (1) 225-232; DOI: https://doi.org/10.1124/mol.60.1.225

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    Research ArticleArticle

    Mechanism of Mitotic Block and Inhibition of Cell Proliferation by the Semisynthetic Vinca Alkaloids Vinorelbine and Its Newer Derivative Vinflunine

    Vivian K. Ngan, Krista Bellman, Bridget T. Hill, Leslie Wilson and Mary Ann Jordan
    Molecular Pharmacology July 1, 2001, 60 (1) 225-232; DOI: https://doi.org/10.1124/mol.60.1.225
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