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Adenocarcinoma cells exposed in vitro to Navelbine or Taxol increase Ep-CAM expression through a novel mechanism

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Abstract

Ep-CAM antigen expression was shown to vary by phase across the cell cycle. Following pretreatment of various adenocarcinoma cells in culture with clinically relevant concentrations of vinorelbine tartrate (Navelbine) or paclitaxel (Taxol), cell surface expression of Ep-CAM antigen increased by two- to ten-fold compared to that of untreated control cells and was associated with arrest of cell cycle progression and accumulation of cells in the S and G2/M phases. We demonstrated that increases in cell surface antigen expression resulted in improved biological effectiveness of the targeting antibody as measured in vitro by antibody-dependent cellular cytotoxicity and in vivo by enhanced antibody targeting to Ep-CAM-expressing xenografts in mice pretreated with Navelbine. No effect on cell cycle progression or Ep-CAM antigen expression was seen with human interferon-α and interferon-γ, agents that increase gene expression of various tumor and normal antigens and may upregulate some antigens. Thus, the upregulation of cell surface Ep-CAM expression following pretreatment with G2/M blockers is through a novel mechanism involving residence time of the antigen on the cell surface. This significant increase in Ep-CAM expression appears to be tumor-specific since we saw no increase in antigen expression on normal epithelial cells. Studies to reveal relative internalization rates suggest that the increase in cell surface expression of Ep-CAM following pretreatment with G2/M blockers is a consequence of an inhibition of normal cycles of antigen endocytosis and expression on the cell surface. The present work provides a mechanism for the improved clinical efficacy of therapeutic antibodies used in combination with traditional cell cycle-specific chemotherapeutic drugs.

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Acknowledgements

The authors would like to acknowledge Tom Lampkin and Neil Spector for their encouragement of this investigation and for critically reading the manuscript. The authors appreciate the statistical analysis of the listmode flow cytometry data by Lei Zhu.

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Authors and Affiliations

  1. Department of Translational Medicine and Technology, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709, USA

    Linda M. Thurmond

  2. Department of Systems Research, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709, USA

    Julie B. Stimmel

  3. Department of Cancer Biology, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709, USA

    Doris M. Murray & Derek J. Eberwein

  4. Department of High Throughput Biology, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709, USA

    Sam M. Witherspoon

  5. Department of Information Analysis, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709, USA

    Vincent C. Knick

  6. Parexel, Inc., 12300 Twinbrook Pkwy, Suite 315, Rockville, MD 20852, USA

    Adrienne C. Ingram

  7. Amgen Inc, 4000 Nelson Road, Mailstop AC-22D, Longmont, CO 80503, USA

    Christian H. Ryan

Authors
  1. Linda M. Thurmond
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  2. Julie B. Stimmel
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  3. Adrienne C. Ingram
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  4. Christian H. Ryan
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  5. Doris M. Murray
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  6. Derek J. Eberwein
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  8. Vincent C. Knick
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Corresponding author

Correspondence to Julie B. Stimmel.

Additional information

The novel mechanism described here is the subject of International Patent WO/01/07082 published 1 February 2001.

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Thurmond, L.M., Stimmel, J.B., Ingram, A.C. et al. Adenocarcinoma cells exposed in vitro to Navelbine or Taxol increase Ep-CAM expression through a novel mechanism. Cancer Immunol Immunother 52, 429–437 (2003). https://doi.org/10.1007/s00262-003-0386-7

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  • DOI: https://doi.org/10.1007/s00262-003-0386-7

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