Selection of drucrs against ovarian cancer and trial of discovering new molecular targets using gene expression profiles

点击翻译按钮获取中文摘要

To clarify genes that play critical roles for carcinogenesis steps and acquisition of drug resistance of ovarian cancer, we studies approximately 6,000 gene expressions using an oligonucleotide microarray system. Gene expression patterns were analyzed by clustering technique, which standardized the gene expression level in normal ovarian tissues. With written informed consent, ovarian cancer tissues from surgical specimens were frozen at-80 C and mRNA was extracted from the tissues. Clustered gene expression profiles of ovarian cancer tissues were clearly different from those of normal tissues. However. there were no significant differences among each histological subtype of cancers. The expression levels of 97 genes were commonly up-regulated in cancer tissues and those of 227 genes were down-regulated. Among these genes, cytokeratin18, Am-1=Evil, HER3, keratin19, ear-2, βtubulin, GSTπ, c-erb-B2, nm23, BRCA2, p57, IGFBP5.6, Brush-1 and TGFB1BP were thought to become a molecular target … More of developng new anti-cancer drugs. One of highly effective drugs against ovarian cancer, paclitaxel, acts as a mitotic spindle poison, i.e., paclitaxel promotes assembly of tubulins and stabilizes them, preventing depolymerization. Our results that βtsubulin was up-regulated in all cancer specimens gave a theoretical evidence to the application of paclitaxel against ovarian cancer treatment. Then, we studied gene expression profiles of human ovarian cancer cell, KF28, Drug-resistant subclones of KF2B were prepared, KFr13, which is resistant to cis-platinum and, KF28TX and KFr13TX, which are resistant to paclitaxel. The cis-platinum-resistant clone showed the high expression of genes related with depoisoning pathway through glutathione, with glycolysis/ glycogenesis, with transketolase and with polyamine synthesis enzymes. The paclitaxel-resistant clones highly expressed multiple drug resistant genes, MDR and semaphorinE, etc. Comparison of clinical factors with expression levels of genes identified in this study will help to develop new molecular target drugs and to clarify mechanism of the acquisition of drug resistance. Less