| Summary: | 碩士 === 國立嘉義大學 === 生化科技研究所 === 97 === Lung cancer is a common malignant tumor in human. The main types of lung cancer are non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC). Target therapy is the common modality to treat lung cancer in the present. There are several manners to inhibit EGFR signaling, such as inhibiting the intracellular tyrosine kinase activity or targeting the extracellular ligand-binding region of EGFR to treat lung cancer. Gefitinib (IressaR, ZD1839) is a selective epidermal growth factor receptor tyrosine kinase inhibitor, which inhibits extracellular signal-regulated kinases 1/2 (ERK1/2) signaling activation to suppress cellular proliferation, and angiogenesis, and promotes apoptosis. Abnormal expression of Rad51 has been reported in various carcinomas with elevated rates of homologous recombination. However, the role of Rad51 in resistance to chemotherapeutic agents and gefitinib in lung cancer cell is unclear. Cisplatin is widespread applied to treat a variety of cancers, including ovarian cancer, sarcomas, lymphomas, germ cell tumors, small cell lung cancer and NSCLC. Mitomycin C (MMC) is one of the first-generation drugs to combine with cisplatin for advanced NSCLC with improving survival. Our results reveal that chemotherapeutic agents such as cisplatin and MMC can enhance Rad51 expression and ERK1/2 activation, which may be the reasons for treatment failure by drug resistance in NSCLC. However, blocking cisplatin and MMC-elicited ERK1/2 activation by gefitinib could decrease Rad51 expression. The results indicate that Rad51 protein can protect lung cancer cells from synergistic cytotoxic effects induced by gefitinib and chemotherapeutic agents. Suppression of Rad51 protein expression might be a novel and important therapeutic modality in human lung cancer which is resistant to EGFR inhibitor and cytotoxic agents.
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