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Cytogenetic Alterations Associated with P-Glycoprotein- and Non-P-Glycoprotein-mediated Multidrug Resistance in SW-1573 Human Lung Tumor Cell Lines¹

Institute of Human Genetics, Free University [A. W. M. N., H. J.], and Division of Molecular Biology, The Netherlands Cancer Institute [F. B.], Amsterdam, and Department of Cytochemistry and Cytometry, University of Leiden, Leiden [J. W.], the Netherlands

Multidrug resistance can be induced in mammalian cells by selection with a single cytotoxic agent. Overproduction of the energy-dependent drug efflux pump P-glycoprotein, encoded by the mdr1 gene, has been identified as the cause of one form of multidrug resistance. The molecular basis of other forms of multidrug resistance is unknown. Doxorubicin selection of the human squamous lung cancer cell line SW-1573 resulted in multidrug-resistant sublines in which a non-P-glycoprotein-mediated form of multidrug resistance precedes mdr1 expression. Here we present a cytogenetic analysis of both non-P-glycoprotein-mediated multidrug-resistant and P-glycoprotein-mediated multidrug-resistant sublines derived from SW-1573. Three independently derived non-P-glycoprotein-mediated multidrug-resistant sublines showed a heterozygous deletion of the short arm of chromosome 2 (p23-pter), whereas alterations of chromosome 7 were present in the P-glycoprotein-mediated multidrug-resistant cell lines. In one series of clonally derived P-glycoprotein-mediated multidrug-resistant sublines, mdr1 overexpression was accompanied by various markers of chromosome 7 with breakpoints at 7q22, the mdr1 gene being known to be located at 7q21.1. Our data suggest that in SW-1573 cells acquisition of non-P-glycoprotein-mediated multidrug resistance is accompanied by a specific deletion or a translocation involving the short arm of chromosome 2, whereas in the emergence of P-glycoprotein-mediated multidrug resistance a rearrangement of the long arm of chromosome 7 is a critical event.

¹ This study was supported by Dutch Cancer Society Grant IKA-VU-84-14 (A. N., H. J.) and a grant from the Netherlands Organization for Scientific Research (F. B.).

² To whom requests for reprints should be addressed, at Cytogenetics Laboratory, Free University Hospital, P. O. Box 7057, NL-1007 MB Amsterdam, the Netherlands.

³ Present address: Division of Neurology, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.

Received 10/10/91. Accepted 6/ 9/92.