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Cross-Resistance to Rhodamine 123 in Adriamycin- and Daunorubicin-resistant Friend Leukemia Cell Variants¹

Département de Pharmacologie Cellulaire, Moléculaire et de Pharmacocinétique, Institut de Cancerologie et d'Immunogenetique (Centre National de la Recherche Scientifique LA-149), Hópital Paul-Brousse, 94804 Villejuif, France [H. T., J.-N. M., A. F.], and University of Miami School of Medicine, Comprehensive Cancer Center for the State of Florida, Miami, Florida 33101 [T. J. L.]

Cross-resistance to rhodamine 123 (Rho-123) has been found in Adriamycin (ADM)-resistant and daunorubicin (DNR)-resistant Friend leukemia cell variants. Cytotoxicity in sensitive cells correlates with the intracellular amount of Rho-123, as determined by high-pressure liquid chromatography. Differential resistance coincides with Rho-123 accumulation which in sensitive cells was 20-fold higher than in resistant cells after 180 min of treatment. Sodium azide, which has been shown to inhibit ADM efflux and consequently increase drug accumulation in ADM-resistant cells, did not inhibit Rho-123 efflux. The difference in Rho-123 accumulation between sensitive and resistant cells correlates with cytotoxicity, which is in contrast to what has been found in these cells when treated with either ADM or DNR.

Moreover, in contrast to the known effects of ADM and DNR on macromolecular synthesis, Rho-123 in sensitive cells was found to inhibit protein synthesis but had no effect on DNA or RNA synthesis. At Rho-123 doses which inhibited protein synthesis, drug localization changed from mitochondrial specific to generalized cytoplasmic. This effect was never achieved in resistant cells, even with prolonged drug exposure.

The relevance of these findings is that different mechanisms of resistance to different drug types can be identified in the same cells even though similar resistance occurs. The similarity in resistance need not share a common mechanism. Although the drugs are effluxed more efficiently in resistant cells, the mechanisms for resistance in each case seem to differ. In the case of ADM and DNR, it appears to be multifactorial, whereas with Rho-123, total intracellular accumulation seems to be most important.

¹ Supported by Institut National de la Santé et de la Recherche Médicale Grant CRL 822034, Association de la Recherche sur le Cancer, and NIH Grant CA 3710901.

² To whom requests for reprints should be addressed.

Received 3/19/84. Accepted 8/17/84.