In vivo and in vitro antitumor activity of oxaliplatin in combination with cetuximab in human colorectal tumor cell lines expressing different level of EGFR
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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DOI：
10.1007/s00280-005-0123-3
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发表时间：
2006-06-01
影响因子：
3
通讯作者：
Allal, C
中科院分区：
文献类型：
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作者：
Balin-Gauthier, D;Delord, JP;Allal, C
本研究旨在评估西妥昔单抗（C225，Erbitux (R)，一种嵌合抗表皮生长因子受体 (EGFR) 单克隆抗体）与奥沙利铂联合体外和体内对表达不同水平 EGFR 的四种结肠癌细胞系（HCT-8、HT-29、SW620、HCT-116）的影响。在体外，西妥昔单抗联合奥沙利铂显着降低了HCT-8（EGF-R中度）和HT-29（EGF-R弱）细胞系中奥沙利铂的IC50值，而SW620（EGF-R阴性）和HCT-116（EGFR强）细胞系仍然无反应。该组合在 HCT-8 和 HT-29 细胞系中具有协同作用，而西妥昔单抗在 HCT-116 或 SW620 细胞系中未引起奥沙利铂 IC50 的重大改变。然后，我们确定了西妥昔单抗对 EGF 诱导的 EGFR 磷酸化的影响，并强调了磷酸化 EGFR 的基础水平与组合反应之间的相关性。在体内，与奥沙利铂（Td分别= 12.6 +/- 2.3和14.4 +/- 3.2天）或西妥昔单抗相比，西妥昔单抗加奥沙利铂的组合显着抑制HCT-8和HT-29的肿瘤生长（肿瘤延迟或Td分别= 21.6 +/- 2.9和18.0 +/- 2.9天，协同效应）在异种移植模型中单独使用（Td 分别为 13.4 +/- 2.9 和 14.5 +/- 2.4 天）。该组合对 HCT-116 和 SW-620 细胞系没有影响。观察到的反应严格取决于细胞类型，与 EGFR 表达水平无关，但与磷酸-EGFR 的基础水平相关。这项研究为奥沙利铂联合西妥昔单抗联合治疗化疗难治性结直肠肿瘤的可能临床研究提供了有希望的临床前结果。
This study aimed to assess the effect of cetuximab (C225, Erbitux (R), 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.