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Atypical Multiple Drug Resistance in a Human Leukemic Cell Line Selected for Resistance to Teniposide (VM-26)¹

Department of Biochemical and Clinical Pharmacology [M. K. D., W. T. B.] and Pharmacokinetics and Pharmacodynamics Section, Pharmaceutical Division [J. C. Y.], St. Jude Children's Research Hospital, Memphis, Tennessee 38101

Resistance to the cytotoxic effects of many natural product drugs after exposure to a single agent is a common observation. The classes of drugs included in the "classic" multiple drug resistance phenotype are Vinca alkaloids, anthracyclines, epipodophyllotoxins, and antibiotics. We report here the characterization of a human leukemic cell line (CEM/VM-1) with "atypical" multiple drug resistance: despite resistance and cross-resistance to etoposide, anthracyclines, mitoxantrone, and 4'-[(9-acridinyl)amino]methanesulphon-m-anisidide (mAMSA), these cells retain sensitivity to the Vinca alkaloids. Further, even though this cell line is 40-fold cross-resistant to the cytotoxic effect of etoposide (VP-16), it is similar to drug-sensitive CEM cells in the cellular pharmacology of [³H]VP-16 as determined by zero time binding, initial influx rate, steady state drug concentration, and unidirectional efflux. Our studies suggest that the resistance of CEM/VM-1 cells to epipodophyllotoxins is due to an altered interaction between drug and its cellular target(s) by a mechanism unrelated to the decreased cellular concentration of drug associated with the "classic" multiple drug resistance phenotype.

¹ Supported in part by Research Grant CA30103 (to W. T. B.) and Cancer Center Support (CORE) Grant CA21765, from the National Cancer Institute, Bethesda, MD; by National Research Service Award CA06795 (to M. K. D.) from the National Cancer Institute; and by American Lebanese Syrian Associated Charities.

² Leukemia Society of America, Special Fellow; Recipient of Biomedical Research Support Grant RR05584-21 from NIH.

³ To whom requests for reprints should be addressed, at St. Jude Children's Research Hospital, Department of Biochemical and Clinical Pharmacology, 332 North Lauderdale, P.O. Box 318, Memphis, TN 38101.

Received 8/15/86. Revised 11/20/86. Accepted 12/ 4/86.

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