Analysis of individual difference of an epidermal growth factor receptor downstream signal system

目的是详细研究EGFR下游信号系统的作用，以澄清除EGFR基因变异之外的决定药物敏感性的因素，并考虑到病程中存在遗传个体差异。我们设计了临床试验，将厄洛替尼作为野生型EGFR基因非小细胞肺癌患者的二线治疗方案，并通过基因芯片和RT-PCR进行生物标志物搜索，验证了从超声内窥镜(EBUS)下穿刺物的微小活检样本中提取高纯度肿瘤RNA的可能性，建立了从临床样本中高效进行DNA微阵列分析的方法。此外，使用非小细胞肺癌细胞和间皮瘤细胞株进行了基础研究，目的是阐明与厄洛替尼疗效相关的生物学意义。胸苷合成酶的表达与培美曲塞的耐药性并不一定相关。二甲双胍对不同组织学类型的人肺癌细胞株的增殖有抑制作用，可能通过诱导细胞凋亡和G0/G1期阻滞等多种机制发挥作用。

The purpose is to examine the role of a downstream signal system of EGFR in detail for clarifying factors other than the EGFR gene variation which determines the susceptibility of the medicine, and considering existence of the hereditary individual difference of the course. We planned clinical trial which prescribes erlotinib for the patient as second line treatment for a non-small-cell-lung-cancer case with a wild type EGFR gene, and performingbiomarker search by a cDNA microarray and RT-PCR.It checked that RNA extraction of the high purity of a tumor was possible from the minute biopsy sample of puncture under the ultrasound endoscopy (EBUS), and established the method of conducting DNA microarray analysis efficiently from a clinical sample. Furthermore, fundamental study was performed using the non-small-cell-lung-cancer-cells and mesothelioma-cells stock for the purpose of clarifying biological significance relevant to the effect of Erlotinib. Thymidylate synthase expression did not necessarily correlate with pemetrexed resistance. Metformin inhibited the proliferation of various histological types of human lung cancer cell lines, possibly by varied mechanisms including apoptosis induction and G0/G1 arrest according to the cell line.