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Resistance to N-Benzyladriamycin-14-valerate in Mouse J774.2 Cells: P-Glycoprotein Expression without Reduced N-Benzyladriamycin-14-valerate Accumulation¹

Departments of Pharmacology [L. L., T. W. S., M. I.] and Medicine [M. E. D.], College of Medicine, and Cancer Center [L. L., T. W. S., M. I.], University of Tennessee-Memphis, Memphis, Tennessee 38163

N-Benzyladriamycin-14-valerate (AD 198) is a highly lipophilic analogue of Adriamycin with novel cytotoxic mechanisms, greater in vivo antitumor activity, and the ability to circumvent multidrug resistance due to P-glycoprotein-mediated drug efflux or decreased topoisomerase II activity. To identify the mechanism(s) which may confer AD 198 resistance, J774.2 mouse macrophage-like cells were selected for growth in cytotoxic levels of AD 198 (AD 198^R). AD 198^R cell exhibited over-expression of the mdr1b (P-glycoprotein) gene, cross-resistance to Adriamycin and vinblastine, and potentiation of drug cytotoxicity by verapamil. However, net intracellular accumulation of AD 198 in AD 198^R cells was unchanged compared to parental cells, while Adriamycin and vinblastine accumulations were reduced 40% and 95%, respectively. AD 198 was localized in the perinuclear region of the cytoplasm in both parental and AD 198^R cells, with additional vesicular compartmentalization in AD 198^R cells. Verapamil-induced reversal of AD 198 resistance coincided with some drug redistribution from cytoplasmic vesicles, but without redistribution of AD 198 into the nucleus. These results suggest that AD 198 resistance was not conferred through a P-glycoprotein-mediated reduction in intracellular drug accumulation but through other cytoplasmic mechanisms, including, but not limited to, drug compartmentalization.

¹ Supported in part by American Cancer Society Grants IN-176-A and JFRA-287 (L. L.), Pharmaceutical Manufacturers Association Foundation Research Starter Grant (L. L.), and NIH-National Cancer Institute Research Grants CA44890 (T. W. S.), CA37082 (M. I.), and CA37209 (M. I.).

² To whom requests for reprints should be addressed, at Department of Pharmacology, University of Tennessee College of Medicine, 874 Union Avenue, Memphis, TN 38163.

Received 3/11/91. Accepted 4/ 3/92.

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