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The Journal of Bone and Joint Surgery 78:366-75 (1996)
© 1996 The Journal of Bone and Joint Surgery, Inc.

Experimental Models for the Study of Drug Resistance in Osteosarcoma: P-Glycoprotein-Positive, Murine Osteosarcoma Cell Lines*

HIDEYUKI TAKESHITA, M.D.{dagger}, MARK C. GEBHARDT, M.D.{ddagger}, DEMPSEY S. SPRINGFIELD, M.D.{ddagger}, KATSUYUKI KUSUZAKI, M.D.§ and HENRY J. MANKIN, M.D.{ddagger}, BOSTON, MASSACHUSETTS

Investigation performed at the Orthopaedic Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston

P-glycoprotein is an adenosine triphosphate-dependent drug-efflux pump that extrudes drugs from cells and causes drug resistance. P-glycoprotein is believed to mediate drug resistance in a wide variety of tumors. In this study, we developed two P-glycoprotein-positive, murine osteosarcoma cell lines that were resistant to Adriamycin (doxorubicin) (MOS/ADR1 and MOS/ADR2). We created the cell lines by short-term pulse exposures of the parent cell line to Adriamycin followed by single-cell cloning. The MOS/ADR1 and MOS/ADR2 cells were sevenfold and eighteenfold more resistant to Adriamycin than the cells from the parent line. Expression of P-glycoprotein, as examined with an immunofluorescence method, was detected in most of the MOS/ADR1 and MOS/ADR2 cells but not in the parent cells. After the cells had been incubated with Adriamycin for one hour, there was less accumulation of the drug in the resistant cell lines than in the parent cell line. The reduced accumulation was due to the increased efflux of Adriamycin. The Adriamycin-resistant cell lines demonstrated greater alkaline phosphatase activity than the parent cell line and produced more differentiated osteoblastic sarcomas in mice. Dose-survival studies with use of a tetrazolium colorimetric assay showed that the MOS/ADR1 cells were cross-resistant to vincristine, vinblastine, etoposide, bleomycin, mitomycin C, and actinomycin D but not to dacarbazine, cisplatin, carboplatin, cytosine arabinoside, carmustine, cyclophosphamide, ifosfamide, methotrexate, and 5-fluorouracil. Although the MOS/ADR2 cells exhibited a similar spectrum of cross-resistance, they were more resistant than the MOS/ADR1 cells. We also tested the effect of three different resistance-modifying agents on the reversal of resistance to Adriamycin. We found that verapamil and trifluoperazine substantially reversed resistance to Adriamycin in the P-glycoprotein-positive cell lines, whereas cyclosporin A was relatively ineffective. Because these cell lines retain the histological and biochemical features of bone-producing sarcomas and display the multidrug-resistant phenotype, they may be useful models for additional investigations of drug resistance in osteosarcoma. CLINICAL RELEVANCE: Recent investigations have shown that tumor cells have energy-dependent, so-called pump mechanisms in their membranes that actively transport certain classes of chemotherapeutic drugs from the cells, rendering them resistant to treatment. At least some human osteosarcomas possess one of these pumps, the P-glycoprotein pump, and this pump may be partially responsible for the observed drug resistance in the current treatment regimens for osteosarcoma. These newly described P-glycoprotein-positive multidrug-resistant osteosarcoma cell lines are useful models for the further characterization of drug resistance in osteosarcoma and for the development of treatment protocols.


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