A STUDY OF CROSS-RESISTANCE PATTERN AND EXPRESSION OF MOLECULAR MARKERS OF MULTIDRUG-RESISTANCE IN A HUMAN SMALL-CELL LUNG-CANCER CELL-LINESELECTED WITH DOXORUBICIN

A doxorubicin-resistant variant of the human small-cell lung-cancer ce ll line N592 was selected by in vitro continuous exposure to increasin g drug concentrations. The aim of this study was to examine the cross- resistance pattern, cellular pharmacokinetics of doxorubicin and expre ssion of molecular factors of resistance. The sub-line N592/DX exhibit ed a multidrug-resistance phenotype, which was somewhat atypical, sinc e it included cisplatin. Development of doxorubicin resistance could n ot be attributed to differential doxorubicin uptake or retention. Vera pamil partially reverted doxorubicin resistance without affecting cell ular pharmacokinetics. These findings are consistent with undetectable levels of mdr-1-gene expression in these cells. A molecular analysis of other putative mechanisms of multidrug resistance indicated no alte rations in GSH levels or GSH-related enzymes, but a marginal reduction of topoisomerase II alpha expression in the resistant sub-line. This reduction, which was associated with an increase in topoisomerase I, d oes not explain the high degree of resistance. This study supports the view that alternative, unidentified mechanisms, which may be of clini cal relevance, must be involved in the development of multidrug resist ance of small-cell lung cancer.