Search for the novel therapy against small cell lung cancer based on the Rb and p53 pathways.

小细胞肺癌（SCLC）约占所有肺癌的15%，并且在癌发生过程中，p53和Rb基因的失活以及用于神经内分泌分化的转录因子的激活被认为是重要的。在本研究中，我们使用20个肺癌细胞系检测了被认为参与肺癌干细胞向小细胞肺癌分化的Ash 1基因和notch基因家族的基因的mRNA表达，并检测了表达与化疗敏感性之间的关系。真实的RT-PCR显示，小细胞肺癌（SCLC）细胞系中Ash 1和Notch 1的表达高于非小细胞肺癌（NSCLC）细胞系。Notch 2和3的表达低于NSCLC。notch基因家族成员之一的mRNA表达与拓扑异构酶抑制剂的化疗敏感性显著相关。 ...更多信息 f在用表达野生型p53的腺病毒（Ad-p53）和/或表达野生型Rb的腺病毒（Ad-Rb）感染的SCLC细胞系中用于神经内分泌分化的转录因子。环巴胺是一种抑制声屏障信号的药物，它被认为参与了肺癌干细胞和小细胞肺癌的建立和维持。我们研究了环巴胺与Ad-p53和Ad-Rb在SCLC细胞中的组合效应。出乎意料的是，大多数SCLC细胞系对环巴胺具有抗性。环巴胺与Ad-p53或Ad-Rb联合应用对SCLC细胞的作用是相加-拮抗作用。EGFR突变3例，病理诊断为混合型小细胞肺癌。这一结果表明，在小细胞肺癌的分子发病机制中，存在一条来自肺腺癌的去分化途径。少

Small cell lung cancer (SCLC) accounts for about 15% of all lung cancer and during the carcinogenesis inactivation of the p53 and Rb genes as well as activation of the transcription factors for neuroendocrine differentiation have been thought to be important. In this study, using in 20 lung cancer cell lines we examined the mRNA expression of the Ash1 gene and the genes of the notch gene family which have been thought to be involved in the differentiation to the small cell lung cancer from lung cancer stem cells, and also examined the relationship between the expressions and chemosensitivity. Real time RT-PCR revealed that the expressions of the Ash1 and Notch1 in SCLC cell lines were higher than those in non-small cell lung cancer (NSCLC) cell lines. The expressions of Notch 2 and 3 were lower than those in NSCLC. The mRNA expression of one of the notch gene family members was significantly correlated with chemosensitivity of topoisomerase inhibitors.We next examined mRNA expression o … More f the transcription factors for neuroendocrine differentiation in SCLC cell lines infected with adenovirus expressing wild-type p53 (Ad-p53) and/or adenovirus expressing wild-type Rb (Ad-Rb). The decline of the mRNA expression during the time-course seemed to be due to apoptosis of the infected cells.Cyclopamine is an inhibitor of the sonic hedghog signaling which is thought to be involved in the establishment and maintenance of the lung cancer stem cells and SCLC. We examined the combinatorial effect of cyclopamine with Ad-p53 and Ad-Rb in SCLC cells. Unexpectedly, majority of SCLC cell lines were resistant to cyclopamine. The combinatorial effects of cyclopamine with Ad-p53 or Ad-Rb to SCLC cells were additive-antagonistic.We searched for the mutations of the epidermal growth factor receptor (EGFR) gene in 110 small cell lung cancer tissues. There were 3 EGFR-mutated cases, which were classified as combined-type small cell lung cancer in pathology. This result suggests that there is a dedifferentiation pathway from lung adenocarcinoma in the molecular pathogenesis of SCLC. Less