Liu Zhiwen, Klominek Julius
Department of Clinical Immunology, Karolinska Institute at Huddinge University Hospital, SE-141 86 Stockholm, Sweden.
Neoplasia. 2004 Nov-Dec;6(6):705-12. doi: 10.1593/neo.04271.
The epidermal growth factor receptor (EGFR) is expressed in a variety of human solid tumors, including malignant mesothelioma. EGFR has been implicated in regulation of cell proliferation, survival, angiogenesis, and metastasis, making it an ideal target for drug development. ZD1839 (gefitinib) and OSI-774 (erlotinib) are new, low-molecular-weight, EGFR-selective tyrosine kinase (TK) inhibitors, whereas CI-1033 is a pan-EGFR family TK inhibitor. In the present study, we used ZD1839, OSI-774, and CI-1033 and investigated the effect of these drugs on proliferation, migration, and matrix metalloprotease (MMP) production in three malignant mesothelioma cell lines (M14K, ZL34, and SPC212). Using [3H]thymidine incorporation, DNA synthesis assay, we found that all three drugs inhibited transforming growth factor-alpha (TGF-alpha)-induced cellular proliferation in a dose-dependent manner. In addition, all three drugs induced apoptosis in ZL34 cells as determined by flow cytometry using annexin-V staining. Furthermore, all three drugs inhibited TGF-alpha-induced cell migration (chemotaxis) in a dose-dependent manner as determined by Boyden chamber assay. TGF-alpha-induced MMP-9 production was also inhibited in a dose-dependent manner as determined by gelatin zymography in three cell lines tested. In conclusion, our study demonstrates inhibitory effectiveness of EGFR-TK inhibitors in malignant mesothelioma cells and suggests that these drugs may be an effective treatment strategy for malignant mesothelioma.
表皮生长因子受体（EGFR）在包括恶性间皮瘤在内的多种人类实体瘤中均有表达。EGFR与细胞增殖、存活、血管生成和转移的调控有关，这使其成为药物开发的理想靶点。ZD1839（吉非替尼）和OSI - 774（厄洛替尼）是新型的低分子量、EGFR选择性酪氨酸激酶（TK）抑制剂，而CI - 1033是一种泛EGFR家族TK抑制剂。在本研究中，我们使用ZD1839、OSI - 774和CI - 1033，研究了这些药物对三种恶性间皮瘤细胞系（M14K、ZL34和SPC212）的增殖、迁移和基质金属蛋白酶（MMP）产生的影响。通过[3H]胸腺嘧啶核苷掺入法（DNA合成测定），我们发现这三种药物均以剂量依赖的方式抑制转化生长因子 - α（TGF - α）诱导的细胞增殖。此外，通过使用膜联蛋白 - V染色的流式细胞术测定，这三种药物均诱导ZL34细胞凋亡。此外，通过Boyden小室测定法确定，这三种药物均以剂量依赖的方式抑制TGF - α诱导的细胞迁移（趋化性）。通过明胶酶谱法在三种测试细胞系中测定，TGF - α诱导的MMP - 9产生也以剂量依赖的方式受到抑制。总之，我们的研究证明了EGFR - TK抑制剂对恶性间皮瘤细胞具有抑制作用，并表明这些药物可能是治疗恶性间皮瘤的有效策略。
