Amplification and expression of mdr genes and flanking sequences in verapamil hypersensitive hamster cell lines

The properties of several multidrug resistant (MDR) Chinese hamster ovary (CHO) cell lines which are verapamil hypersensitive have been investigated, extending our earlier study of two such cell lines. It was observed that increasing levels of multidrug resistance are associated with increasing verapamil and nicardipine sensitivity, although the cell lines are not hypersensitive to cyclosporin A. Although there is appreciable amplification of the P-glycoprotein gene at higher levels of multidrug resistance/verapamil hypersensitivity, there is only very low or no amplification of five flanking genes, including the sorcin gene. Low levels of resistance (3-10 fold) appear to involve increased P-glycoprotein gene expression at the level of transcription. P-glycoprotein levels of the cell lines have been measured by flow cytometry using the monoclonal antibody C219, and there is a general correlation between P-glycoprotein overexpression, increased levels of the corresponding mRNA and the level of verapamil hypersensitivity.