RESUMEN
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.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antígenos de Neoplasias/metabolismo , Antineoplásicos Fitogénicos/farmacología , Biomarcadores de Tumor/metabolismo , Moléculas de Adhesión Celular/metabolismo , Paclitaxel/farmacología , Vinblastina/análogos & derivados , Vinblastina/farmacología , Adenocarcinoma/metabolismo , Animales , Supervivencia Celular/efectos de los fármacos , Cromo/metabolismo , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Molécula de Adhesión Celular Epitelial , Femenino , Fase G2/efectos de los fármacos , Humanos , Técnicas In Vitro , Lutecio/química , Lutecio/farmacocinética , Masculino , Ratones , Ratones Desnudos , Mitosis/efectos de los fármacos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Células Tumorales Cultivadas , VinorelbinaRESUMEN
We have identified a novel class of 6-thiazolylquinazolines as potent and selective inhibitors of both ErbB-2 and EGFR tyrosine kinase activity, with IC(50) values in the nanomolar range. These compounds inhibited the growth of both EGFR (HN5) and ErbB-2 (BT474) over-expressing human tumor cell lines in vitro. Using xenograft models of the same cell lines, we found that the compounds given orally inhibited in vivo tumor growth significantly compared with control animals.