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In vivo and in vitro antitumor activity of oxaliplatin in combination with cetuximab in human colorectal tumor cell lines expressing different level of EGFR

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Abstract

This study aimed to assess the effect of cetuximab (C225, Erbitux®, a chimeric anti-epidermal growth factor receptor (EGFR) monoclonal antibody) in combination with oxaliplatin in vitro and in vivo on four colon cancer cell lines (HCT-8; HT-29, SW620, HCT-116) expressing different levels of EGFR. In vitro, cetuximab combined with oxaliplatin significantly decreased the IC50 values of oxaliplatin in HCT-8 (EGF-R moderate) and HT-29 (EGF-R weak) cell lines, while SW620 (EGF-R negative) and HCT-116 (EGFR strong) cell lines remained unresponsive. This combination was synergistic in HCT-8 and HT-29 cell lines while cetuximab induced no major modification of the IC50 of oxaliplatin in HCT-116 or SW620 cell lines. We then determined the effect of cetuximab on the EGF-induced EGFR phosphorylation and we highlight a correlation between the basal level of phospho-EGFR and the response to the combination. In vivo, the combination of cetuximab plus oxaliplatin significantly inhibited tumor growth of HCT-8 and HT-29 (tumor delay or Td = 21.6±2.9 and 18.0±2.9 days respectively, synergistic effect) compared to either oxaliplatin (Td=12.6±2.3 and 14.4±3.2 days respectively) or cetuximab (Td=13.4±2.9 and 14.5±2.4 days, respectively) alone in xenograft models. The combination had no effect on HCT-116 and SW-620 cell lines. The observed responses are strictly dependent on the cell type, and are not correlated with the level of EGFR expression but related to the basal level of phospho-EGFR. This study provides promising preclinical results for a possible clinical investigation of the combination of oxaliplatin plus cetuximab in chemorefractory colorectal tumors.

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Abbreviations

EGFR:

Epidermal growth factor receptor

L-OHP:

Oxaliplatin

FCS:

Fetal calf serum

MAPK:

Mitogen-activated protein kinases

AU:

Arbitrary unit

NER:

Nucleotide excision repair

Td:

Tumor delay

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Acknowledgments

This study was supported by the “Association pour la Recherche sur le Cancer”, and Diane Balin-Gauthier was funded by a grant from “La Ligue Nationale contre le Cancer”. We thank Dr. E. Lazartigues for assistance in the preparation of this manuscript.

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Authors and Affiliations

  1. EA 3035 Laboratoire de Pharmacologie Clinique et Expérimentale des Médicaments Anticancéreux, Université Paul Sabatier, Toulouse, France

    Diane Balin-Gauthier, Jean-Pierre Delord, Valérie Mallard, Fabienne Thomas & Roland Bugat

  2. Institut Claudius Regaud, 20–24, rue du Pont Saint Pierre, 31052, Toulouse Cedex, France

    Jean-Pierre Delord, Philippe Rochaix, Isabelle Hennebelle, Roland Bugat, Pierre Canal & Cuider Allal

Authors
  1. Diane Balin-Gauthier
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  2. Jean-Pierre Delord
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  3. Philippe Rochaix
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  4. Valérie Mallard
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  5. Fabienne Thomas
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  6. Isabelle Hennebelle
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  7. Roland Bugat
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  8. Pierre Canal
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  9. Cuider Allal
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Corresponding author

Correspondence to Cuider Allal.

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Balin-Gauthier, D., Delord, JP., Rochaix, P. et al. In vivo and in vitro antitumor activity of oxaliplatin in combination with cetuximab in human colorectal tumor cell lines expressing different level of EGFR. Cancer Chemother Pharmacol 57, 709–718 (2006). https://doi.org/10.1007/s00280-005-0123-3

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  • DOI: https://doi.org/10.1007/s00280-005-0123-3

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