Non-P-Glycoprotein mediated Mechanism for Multidrug Resistance Precedes P-Glycoprotein Expression during in Vitro Selection for Doxorubicin Resistance in a Human Lung Cancer Cell Line

Two different mechanisms that contribute to multidrug resistance (MDR) were found in derivatives of the human squamous lung cancer cell line SW-1573. The parental cell line has a low amount of mdrl P-glycoprotein mRNA. In three independent selections for doxorubicin resistance, MDR variants arose in which mdrl P-glycoprotein mRNA and protein was not detectable. Selection on higher doxorubicin concentrations gave rise to variants containing high levels of mdrl mRNA, due to transcriptional activation of the mdrl gene. Upon continued selection for higher levels of doxorubicin resistance, the mdrl gene became amplified, resulting in an additional increase in the level of mdrl mRNA. The cross-resistance pattern of the sublines that lack mdrl P-glycoprotein expression is different from that seen in the mdrl overexpressing cells. Both types of MDR cell lines are resistant to doxorubicin, daunorubicin, etoposide, colchicine, gramicidin D, and vincristine. However, in the non-P-glycoprotein-mediated MDR cell lines, resistance levels are lower and a preferential resistance for etoposide is seen.