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Sequential Coexpression of the Multidrug Resistance Genes MRP and mdr1 and Their Products in VP-16 (Etoposide)-selected H69 Small Cell Lung Cancer Cells¹

Department of Pathology [I. B., M. S.], Sundby Hospital, 2300 Copenhagen S, Denmark; Finsen Laboratory [B. S. N.] and Department of Oncology [P. B. J.], The Finsen Centre, Rigshospitalet, 2100 Copenhagen ø, Denmark; and Cancer Research Laboratory and Department of Pathology [D. R. H., R. G. D., S. P. C. C.], Queen's University, Kingston, Ontario, Canada

Resistance to drugs included in the multidrug-resistance phenotype has been attributed to overexpression of either mdr1 or MRP genes and their products in numerous cell lines, while coexpression, to our knowledge, has not previously been reported in the same cells. Human small cell lung cancer H69/VP cells were developed by continuous incubation in increasing doses of VP-16. In reverse transcription-PCR assays we found overexpression of both mdr1 and multidrug-resistance protein (MRP) genes, and immunoblots showed both elevated P-glycoprotein and MRP in H69/VP cells. Double immunocytochemical staining demonstrated the expression of both MRP and P-glycoprotein in the same cells, indicating that the observations do not result from the selection of two independent clones. Examination of early passages of H69/VP cells showed that overexpression of MRP mRNA occurred prior to mdr1. Thus, cell lines and clinical samples in the future should be tested for both mdr1/P-glycoprotein and MRP since a positive result for one of the phenotypes does not preclude the existence of the other.

¹ This work was supported by studentship grants from the Copenhagen City Health Research Council (I. B., B. S. N.) and the Medical Research Council of Canada (D. R. H.), by grants from the Danish Cancer Society (P. B. J., M. S.) and the Medical Research Council of Canada (R. G. D., S. P. C. C.), and by the Georg and Ellen Bjørkner Foundation and the Novo-Nordisk Foundation.

² To whom requests for reprints should be addressed.

Received 11/16/94. Accepted 12/19/94.

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