Antitumor activity of HER1/EGFR tyrosine kinase inhibitor erlotinib, alone and in combination with CPT-11 (irinotecan) in human colorectal cancer xenograft models
Antitumor activity of HER1/EGFR tyrosine kinase inhibitor erlotinib, alone and in combination with CPT-11 (irinotecan) in human colorectal cancer xenograft models
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DOI：
10.1007/s00280-006-0320-8
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发表时间：
2007-04-01
影响因子：
3
通讯作者：
Higgins, Brian
中科院分区：
文献类型：
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作者：
Chen, Jianping;Smith, Melissa;Higgins, Brian
厄洛替尼（Tarceva（（R）），OSI-774）是一种有效的口服小分子HER 1/EGFR酪氨酸激酶活性抑制剂。在本研究中，在无胸腺小鼠的两种人结直肠肿瘤异种移植模型（LoVo和HCT 116）中评价了厄洛替尼的抗肿瘤活性。当厄洛替尼作为单一疗法施用时，在100 mg/kg [TGI > 100%，P < 0.001; 6/10部分消退（PR）]和25 mg/kg（TGI = 79%，P < 0.001）剂量下在LoVo模型中均观察到显著的肿瘤生长抑制（TGI）。然而，HCT 116异种移植模型对任何剂量的厄洛替尼均无反应。这两种肿瘤模型对厄洛替尼的不同反应不是HER 1/EGFR表达水平差异的结果，因为这两种细胞系中的HER 1/EGFR表达水平相似。然而，已经证明，在HCT 116模型中对厄洛替尼的抗性可能是这些肿瘤中ERK持续活化的结果。基于厄洛替尼在LoVo肿瘤中的单药活性，进行了与CPT-11（Camptosar（（R）），伊立替康）的联合研究。CPT-11以60 mg/kg的最佳剂量或15 mg/kg的较低剂量在LoVo荷瘤小鼠中产生显著的TGI（分别为TGI > 100%，P < 0.001和TGI = 93%，P < 0.001）。厄洛替尼（25 mg/kg）和CPT-11（15 mg/kg）联合治疗产生的抗肿瘤活性（TGI > 100%，P < 0.001; 10/10 PR）显著高于任一药物单独治疗（P < 0.05），而毒性没有增加。这些数据表明，在LoVo人结直肠肿瘤异种移植模型中，厄洛替尼可增强CPT-11的抗肿瘤活性，而不增强毒性。
Erlotinib (Tarceva((R)), OSI-774) is a potent, orally available, small-molecule inhibitor of HER1/EGFR tyrosine-kinase activity. In this study, the antitumor activity of erlotinib was evaluated in two human colorectal tumor xenograft models (LoVo and HCT116) in athymic mice. When erlotinib was administered as monotherapy, significant tumor growth inhibition (TGI) was seen in the LoVo model at both 100 mg/kg [TGI > 100%, P < 0.001; 6/10 partial regressions (PRs)] and 25 mg/kg (TGI = 79%, P < 0.001) doses. However, the HCT116 xenograft model was not responsive to any dose of erlotinib tested. The differential response to erlotinib of these two tumor models was not a result of differences in HER1/EGFR expression levels since these were similar in both cell lines. However, it was demonstrated that resistance to erlotinib in the HCT116 model may be a result of persistent activation of ERK in these tumors. Based on the single agent activity of erlotinib in LoVo tumors, a combination study with CPT-11 (Camptosar((R)), irinotecan) was performed. CPT-11 at the optimal dose of 60 mg/kg or a lower dose of 15 mg/kg resulted in significant TGI (TGI > 100%, P < 0.001, and TGI = 93%, P < 0.001, respectively) in LoVo-bearing mice. Combination treatment with erlotinib (25 mg/kg) and CPT-11 (15 mg/kg) produced significantly greater antitumor activity (TGI > 100%, P < 0.001; 10/10 PRs) than either agent alone (P < 0.05), with no increase in toxicity. These data indicate that erlotinib can enhance the antitumor activity of CPT-11, without enhanced toxicity, in the LoVo human colorectal tumor xenograft model.