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Correlation of Multidrug Resistance with Decreased Drug Accumulation, Altered Subcellular Drug Distribution, and Increased P-Glycoprotein Expression in Cultured SW-1573 Human Lung Tumor Cells¹

Institute of Human Genetics [H. G. K., W. G. E. J. S., H. J.] and Departments of Medical Oncology [G. J. S., H. J. B., J. L., H. M. P.] and Radiotherapy [J. v. R.], Free University, Amsterdam, The Netherlands

Four multidrug-resistant variants of the human squamous lung cancer cell line SW-1573 with levels of doxorubicin resistance ranging from 10- to 2000-fold were characterized with respect to drug accumulation and efflux, subcellular drug distribution pattern, antioxidant defenses, and P-glycoprotein expression. For all these parameters except the antioxidant defenses a correlation was observed with the level of doxorubicin resistance; with increasing drug resistance cellular drug accumulation capacity (as measured for doxorubicin) progressively decreased, initial drug efflux rates (as measured for daunorubicin) progressively increased, while the subcellular doxorubicin distribution (as measured by fluorescence microscopy) gradually shifted from a "mainly nuclear" to a "mainly cytoplasmic" pattern. Our data suggest that in the present set of cell lines the same mechanism of resistance is operating at all levels of doxorubicin resistance.

¹ Financial support from The Netherlands Cancer Foundation (Queen Wilhelmina Fund) by Grant IKA VU-84-14 to H.J.; G. J. S. and H. J. B. were supported by Grants IKA VU-88-22 and IKA-VU-85-5.

² Present address: Department of Toxicology, Duphar B.V., P. O. Box 2, 1380 AA Weesp, The Netherlands.

³ To whom correspondence should be addressed, at the Institute of Human Genetics, Free University, P. O. Box 7161, 1007 MC Amsterdam, The Netherlands.

Received 11/18/88. Revised 2/24/89. Accepted 3/ 7/89.

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