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Increased Glutathione Peroxidase Activity in a Human Sarcoma Cell Line with Inherent Doxorubicin Resistance¹

Section of Hematology /Oncology [B. L. S., J. L. M., M. B. C., A. R. S.] and Department of Radiation Oncology [M. A. B., R. R. W.], University of Chicago, Chicago, Illinois 60637, and Medicine Branch, National Cancer Institute, Bethesda, Maryland 20892 [B. K. S., A. J. T.]

Several mechanisms of drug resistance have been defined using cell lines selected for resistance in vitro. However, the relevance of these to tumor cell resistance in vivo remains unclear. We established tumor cell lines from biopsies of human sarcomas before and after doxorubicin therapy. One pretreatment sarcoma line, STSAR90, was 6-fold less sensitive to doxorubicin than was a normal fibroblast line, AG1522. The sensitivities of six other sarcoma lines were similar to that of AG1522. STSAR90 cells did not overexpress P-glycoprotein mRNA, by Northern analysis with the pCHP1 complementary DNA fragment. Photoaffinity labeling with the vinblastine analogue N-(p-azido-3-¹²⁵I-salicyl)-N'-ß-aminoethylvindesine did not show increased P-glycoprotein concentrations. Accumulation of [³H]daunomycin was not decreased in STSAR90 compared with a less resistant sarcoma line, STSAR11, nor was the doxorubicin sensitivity of STSAR90 increased by coincubation with verapamil. Glutathione levels were twice as high in STSAR90 as in STSAR11, and glutathione peroxidase activity was 3.5- to 6-fold higher. This was due mostly to an increase in selenium-dependent peroxidase activity. After exposure to doxorubicin, STSAR90 cells formed only half as much measurable hydroxyl radical as STSAR11, as detected by electron spin resonance spectrometry. Doxorubicin sensitivity was increased in STSAR90 cells when intracellular glutathione levels were reduced by buthionine sulfoximine. These results indicate that multidrug resistance due to P-glycoprotein-mediated drug efflux is not the only mechanism of doxorubicin resistance that occurs in sarcomas and that glutathione peroxidase-dependent detoxification of doxorubicin-induced oxygen radicals may contribute to clinical doxorubicin resistance.

¹ Supported in part by Grants CA 47652 and CA 42596 from the NIH, the Richard L. Duchossois Cancer Research Fund, the Passis Fund, the Center for Radiation Therapy, and Grant ACS IN-41-29 from the American Cancer Society.

² Recipient of an American Cancer Society Physician's Research Training Fellowship and a National Research Service Award. To whom requests for reprints should be addressed, at Section of Hematology/Oncology, Box 420, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637.

Received 5/11/89. Accepted 10/26/90.

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