Study on the multiple drug resistant mechanisms in clinical materials of lung cencer

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Topoisomerase II alpha content, topoisomerase II catalytic activity and drug sensitivities to the topoisomerase inhibitors, doxorubicin, and etoposide, were examined in human lung cencer cell lines to determine the relationship between topoisomerase II and drug sensitivities to the topoisomerase II inhibitors. Moreover, the relationship between these biochemical analyzes and topoisomerase II immunostaining in cytosp=in preparations was examined. The difference in drug sensitivities to doxorubicin and etoposide in human lung cencer cell lines is not explainable by the topoisomerase II alpha levels and topoisomerase II catalytic activity. The percentages of positive cells for topoisomerase II immunostaining are compatible with the levels of topoisomerase II alpha content or topoisomerase II catalytic activity. Our results indicate that topoisomerase II immunostaining can be utilized in place of biochemical analysis. It is difficult to collect sufficient cells for these biochemical analyzes from lung cencer patients by transbronchial brushing or aspiration, or pleural effusions. Therefore, we examined the intracellular drug distribution using a confocal laser scanning microscopy. In this study, the cells with intranuclear drug accumulation are more sensitive than those with extranuclear drug accumulation. Moreover, the resistant cell line showed extranuclear distribution of topoisomerase II enzyme detected by immunostaining method using the confocal laser scanning microscopy. The confocal laser scanning microscopy is useful to detect the drug sensitivity and resistant in clinical samples those are usually small amount.These methods are applied in the patients with malignant pleural effusion after intra-pleural injection of anthracyclines. The patients with intranuclear drug accumulation revealed the good control of malignant effusion. We conclude that this method is useful in the estimation of drug sensitivity of lung cencer cells, especially the clinical materials.