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Characterization of a New Drug-resistant Human Myeloma Cell Line That Expresses P-Glycoprotein¹

Departments of Medicine [W. S. D., B. G. M. D., D. S. A.] and Radiation Oncology [A. E. C.], Cancer Center Division, The University of Arizona, Tucson, Arizona 85724, and The Ontario Cancer Institute, Department of Medical Biophysics [J. H. G.] University of Toronto, Toronto, Ontario, M4X 1K9, Canada

Multiple myeloma is a disease with a high initial chemotherapeutic response but virtually no cures due to emergence of drug resistance. A doxorubicin-resistant human myeloma cell line (8226/Dox) has been selected from the myeloma cell line RPMI8226 by continuously exposing cells to gradually increasing doses of doxorubicin. The resistant phenotype has been retained for over 2 months despite growth in drug-free medium. The resistant subline was cross-resistant to mitoxantrone, acronycine, etoposide, and vincristine. The 8226/Dox cell line remained sensitive to melphalan but acquired collateral sensitivity to dexamethasone. Intracellular doxorubicin accumulation, as measured by [¹⁴C]doxorubicin and high-performance liquid chromatography, was decreased by 54% at 1 h for 8226/Dox compared to the sensitive line. Efflux of doxorubicin was significantly greater in the resistant subline as compared to the sensitive parent cell line. Membrane analysis using immunoblotting techniques detected increased expression of the integral membrane protein P-glycoprotein (M_r 170,000) in the resistant subline. Cytogenetic analysis of 8226/Dox revealed a 7q-anomaly not seen in the parent cell line. No double minutes or homogeneously staining regions were observed. The drug sensitivity/resistance pattern of the resistant cell line correlates well with clinical observations indicating the potential of this cell line as a model for resistance in multiple myeloma.

¹ This study was supported in part by Grants CA-17904, CA-23074, and CA-28139 from the National Cancer Institute and a starter grant from the American Cancer Society, Institutional Review Committee, University of Arizona.

² Recipient of a faculty development award in clinical pharmacology from the Pharmaceutical Manufacturers Association Foundation. To whom requests for reprints should be addressed.

Received 2/28/86. Revised 6/17/86. Accepted 6/20/86.

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