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Institut fur Pathologie, Christian-Albrechts-Universitat zu Kiel, Kiel [M. D., H. L.] and Institut fur Pathologie, Universitat Hamburg [H. A., A. N.], Hamburg, Federal Republic of Germany
A newly established gastric carcinoma cell line (EPG85-257P) exhibited a high sensitivity to mitoxantrone (DHAD) as determined by a monolayer proliferation assay. The concentration to inhibit cell growth to 50% of controls (IC50) was 0.0022 µg/ml culture medium. The cells were continuously incubated for more than 4 months in the presence of stepwise increased concentrations of DHAD, and the IC50 was increased to 0.41 µg/ml, i.e., 186.4-fold. This resistant variant was named EPG85-257RNOV. The EPG85-257RNOV cells became cross-resistant to Adriamycin with enhanced IC50 by 10.5-fold and to daunomycin with enhanced IC50 by 3.9-fold. No distinct resistance was observed to vinblastine, vincristine, and colchicine. Verapamil (10-6, 4 x 10-6 and 10-5 M) and cyclosporin A (10-6, 3 x 10-6 and 10-5 M) did not reverse DHAD resistance. As shown by immunocytochemistry (monclonal antibodies: C219 and JSB-1) and Northern blot analysis, DHAD resistance was not associated with the appearance of the multidrug resistance (MDR)-associated (Mr 170,000) P-glycoprotein or the overexpression of P-glycoprotein mRNA. The data indicate a chemoresistance pattern unlike typical MDR (often called "atypical" MDR).
The phenotypes of parent and resistant EPG85-257 cells were compared using interference contrast microscopy, electron microscopy, and immunocytochemistry. After DHAD application the following structural characteristics were found to be associated with emergence of resistance: (a) intensive formation of surface vesicles in the resistant variant. Such vesicles were almost absent in sensitive cells; (b) the vesicles contained the selecting DHAD which was visualized by its blue color; and (c) in electron microscopy the vesicles were formed by an inner and an outer double membrane, presumably derived from the plasmalemma. These observations suggest a complex cellular mechanism responsible for DHAD resistance which includes formation of membrane vesicles, vesicular drug binding, and drug compartmentalization.
1 This work was supported by the Deutsche Forschungsgemeinschaft, SFB 232 and Di 276/1–3, the Hamburger Stiftung zur Fördereung der Krebsbekämpfung, the Hamburger Landesverband zur Krebsbekämpfung und Krebsforschung, and the E. und G. Roggenbuck-Stiftung. Presented in part at the 18th meeting of the University of California at Los Angeles, Keystone, CO, 1989.
2 To whom requests for reprints should be addressed, at Institut für Pathologie, Christian-Albrechts-Universität, Michaelisstr. 11, D-2300 Kiel, Federal Republic of Germany.
Received 2/23/89. Accepted 6/13/90.
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