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

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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