| Summary: | 碩士 === 高雄醫學大學 === 生物化學研究所 === 88 === The major problem in lung cancer chemotherapy is the emergence of inherent and acquired drug resistance of cancer cells. Lung cancers can be divided into two groups, small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). The treatment of SCLC consists primarily of combination chemotherapy with or without radiotherapy. In contrast to SCLC, NSCLC has the limitations of using chemotherapy for the treatment. The drug-resistance in lung cancers has been extensively studied, including multidrug resistance and DNA repair. However, tumor necrosis factor receptor I and II (TNFR I and II) which are related with cell apoptosis have not been characterized in the drug-resistance of lung cancers. Previous results had shown that the gene expression of TNFR II was greatly depressed comparing with that of normal lung cells, and NSCLC demonstrated a cisplatin-resistance. The down-regulation of TNFR II in lung cancers may lead to incapable of apoptosis and results in drug-resistance of the cells. Therefore, NSCLC cell lines (H596, H441 and H520) were utilized to evaluate the cisplatin-resistance of lung cancer cells. The level of expression of the TNFR I and II was examined by RT-PCR. All the tested NSCLC cells were TNF-a and TNF-b insensitive. The regulation of TNFR I and II genes' expression in response to cisplatin was determined. It was shown that a down-regulation of TNFR I and II gene expression in cisplatin-resistant H441 and H520 cells after cisplatin (160 mM) treatment was observed, while the expression of TNFR I and II in H596 was up-regulated after treatment. The results derived from immunocytochemistry were consistant with those from RT-PCR. In addition, the signal transmitters of TNFR e.g. TRADD and FADD were up-regulated. To verify the role of TNFR in the mechanism of cisplatin-resistance of NSCLC, external TNF-a and TNF-b were added with cisplatin for the treatment of NSCLC cells. The results indicated that the combination of cisplatin and TNF could enhance the cytotoxicity of cisplatin to H596, but there was no effect in cisplatin-resistant H441 and H520 cells. This study demonstrates that TNFR may be involved in the mechanism of cisplatin-resistance of NSCLC.
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