Cooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab (Herceptin) on human breast cancer cell growth
Cooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab (Herceptin) on human breast cancer cell growth
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DOI：
10.1093/annonc/mdf020
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发表时间：
2002-01-01
影响因子：
50.5
通讯作者：
Menard, S
中科院分区：
文献类型：
--
作者：
Normanno, N;Campiglio, M;Menard, S
背景资料：共表达的表皮生长因子受体（EGFR）和ErbB-2被发现在一个子集的原发性人类breast cancer.Materials和方法：抗EGFR和抗ErbB-2剂的抗增殖作用进行了评价，使用单层测定。通过Western blot分析这些药物对EGFR、ErbB-2、AKT和p42/p44 MAP激酶（MAPK）活化的影响。我们发现，ZD 1839（易瑞沙），一种特异性EGFR酪氨酸激酶抑制剂，和曲妥珠单抗，人源化ami-ErbB-2单克隆抗体（赫赛汀）（TRA）能够抑制SK-Br-3和BT-474乳腺癌细胞的生长，其同时表达EGFR和ErbB-2。用ZD 1839和TRA组合处理乳腺癌细胞导致协同抑制作用。用ZD 1839处理SK-Br-3细胞后，EGFR和ErbB-2的酪氨酸磷酸化水平显著降低，且呈剂量依赖性。在用ZD 1839处理后，SK-Br-3细胞中MAPK和AKT的磷酸化显著减少，而用TRA处理产生AKT的减少，但不产生MAPK磷酸化。最后，用ZD 1839处理，而不是TRA处理，在乳腺癌细胞中产生了片段化DNA的显著增加。然而，一个更明显的增加片段化DNA的水平，观察以下结合治疗与ZD 1839和TRA.Conclusions：这些数据表明，结合治疗与药物，靶向EGFR和ErbB-2可能会导致在这些乳腺癌患者的肿瘤共表达两种受体的肿瘤生长的有效抑制。
Background: Co-expression of the epidermal growth factor receptor (EGFR) and of ErbB-2 is found in a subset of primary human breast cancer.Materials and methods: The antiproliferative effects of anti-EGFR and anti-ErbB-2 agents were evaluated using a monolayer assay. The effects of these agents on the activation of EGFR, ErbB-2, AKT and p42/p44 MAP kinases (MAPK) were investigated by western blot analysis.Results: We found that both ZD1839 (Iressa), a specific EGFR tyrosine kinase inhibitor, and trastuzumab (Herceptin) (TRA), a humanized ami-ErbB-2 monoclonal antibody, were able to inhibit the growth of SK-Br-3 and BT-474 breast carcinoma cells, which express both EGFR and ErbB-2. Treatment of breast carcinoma cells with a combination of ZD1839 and TRA resulted in a synergistic inhibitory effect. Treatment of SK-Br-3 cells with ZD1839 produced a significant, dose-dependent reduction of the tyrosine phosphorylation of both EGFR and ErbB-2. Phosphorylation of MAPK and AKT were significantly reduced in SK-Br-3 cells following treatment with ZD1839, whereas treatment with TRA produced a reduction of AKT but not MAPK phosphorylation. Finally, treatment with ZD1839, but not with TRA, produced a significant increase in fragmented DNA in breast carcinoma cells. However, a more pronounced increase in the levels of fragmented DNA was observed following combined treatment with ZD1839 and TRA.Conclusions: These data suggest that combined treatment with drugs that target EGFR and ErbB-2 might result in an efficient inhibition of tumor growth in those breast carcinoma patients whose tumors co-express both receptors.