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Pharmacological and Biological Evidence for Differing Mechanisms of Doxorubicin Resistance in Two Human Tumor Cell Lines¹

Departments of Radiation Oncology [M. L. S., J. M. T.] and Medicine [W. S. D.], Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724; and Department of Blood Banking, Cleveland Clinic Foundation, Cleveland, Ohio 44106 [G. A. H.]

The cellular pharmacology of doxorubicin resistance (DOX^R) has most commonly been associated with decreased drug uptake, enhanced drug efflux, cross-resistance to multiple anticancer agents, and the overproduction of a M_r 170,000 cell surface glycoprotein (termed P-glycoprotein). In this study, the pharmacological and genetic characteristics of two newly derived human DOX^R sublines were examined. These DOX^R sublines were established following continuously increasing DOX exposure until a 222-fold resistant fibrosarcoma subline (HT1080/DR4) and a 285-fold resistant colon adenocarcinoma subline (LoVo/DR5) were developed. However, three major lines of evidence suggest that despite the similar selection strategy, the mechanism of DOX^R differs significantly between these two cell lines. First, Western blotting using the C219 antibody specific to P-glycoprotein revealed the overexpression of the M_r 170,000 cell surface glycoprotein in LoVo DOX^R cells but not in HT1080 DOX^R cells. Second, LoVo DOX^R cells are cross-resistant to vincristine, actinomycin D, colchicine, etoposide, and gramicidin D, but not to 1-ß-D-arabinofuranosylcytosine. In contrast, HT1080 DOX^R cells display cross-resistance to vincristine, actinomycin D, vinblastine, and etoposide; however, they are not cross-resistant to gramicidin D, and show an increased (18-fold) cross-resistance to 1-ß-D-arabinofuranosylcytosine. Third, intracellular DOX accumulation (as measured by [¹⁴C]DOX at 1-h and high-performance liquid chromatography analysis) was decreased 2.7-fold in LoVo DOX^R cells and 2.0-fold in HT1080/DR4 cells. However, while net accumulation studies in the presence of 5 µg/ml verapamil reversed DOX^R to parental values in LoVo colon adenocarcinoma cells, it only minimally decreased DOX resistance (12.6%) in HT1080/DR4 cells. Efflux patterns of [¹⁴C]DOX were similar for the DOX^R sublines with an 50% decrease in DOX retention after 1 h when compared to their respective parental cell lines. Our results suggest that DOX^R in LoVo/DR5 cells may result from overexpression of P-glycoprotein. In contrast, DOX^R in HT1080/DR4 appears to be non-P-glycoprotein mediated and may be related to an alternative mechanism capable of altering drug efflux or differential drug binding.

¹ This study was supported in part by PHHS Grants CA-41183 (J. M. T.) and CA-43043 (W. S. D.).

² Recipient of a Cancer Research Fellowship on behalf of the Ladies Auxiliary of the Veterans of Foreign Wars of the United States. To whom requests for reprints should be addressed at University of Arizona, Cancer Center, 1515 North Campbell Ave., 3rd floor, Tucson, AZ 85724.

³ Scholar of the Leukemia Society of America.

Received 10/ 7/87. Revised 2/11/88. Accepted 2/18/88.

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