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

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-...

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Bibliographic Details
Published in:	Cancer Immunology, Immunotherapy Vol. 52; no. 7; pp. 429 - 437
Main Authors:	THURMOND, Linda M, STIMMEL, Julie B, INGRAM, Adrienne C, RYAN, Christian H, MURRAY, Doris M, EBERWEIN, Derek J, WITHERSPOON, Sam M, KNICK, Vincent C
Format:	Journal Article
Language:	English
Published:	Berlin Springer 01-07-2003 Springer-Verlag
Subjects:	Adenocarcinoma - drug therapy Adenocarcinoma - metabolism Animals Antigens, Neoplasm - metabolism Antineoplastic agents Antineoplastic Agents, Phytogenic - pharmacology Biological and medical sciences Biomarkers, Tumor - metabolism Cell Adhesion Molecules - metabolism Cell Survival - drug effects Chromium - metabolism Colonic Neoplasms - drug therapy Colonic Neoplasms - metabolism Epithelial Cell Adhesion Molecule Female G2 Phase - drug effects Humans Immunotherapy In Vitro Techniques Lutetium - chemistry Lutetium - pharmacokinetics Male Medical sciences Mice Mice, Nude Mitosis - drug effects Original Paclitaxel - pharmacology Pharmacology. Drug treatments Prostatic Neoplasms - drug therapy Prostatic Neoplasms - metabolism Tumor Cells, Cultured Vinblastine - analogs & derivatives Vinblastine - pharmacology Vinorelbine Adenocarcinoma Antineoplastic agent Targeting Antibody Taxol Cell adhesion molecule Malignant tumor Gene expression In vitro Cell surface Antigen Alkaloid Ep-CAM Taxane derivatives Cell cycle Paclitaxel G2 Phase Antigen quantitation Mechanism of action G2/M agents Tumor cell Vinorelbine
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Summary:	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-alpha and interferon-gamma, 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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0340-7004 1432-0851
DOI:	10.1007/s00262-003-0386-7