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Isolation and Characterization of Adriamycin-resistant HL-60 Cells Which Are Not Defective in the Initial Intracellular Accumulation of Drug¹

Division of Biology, Kansas State University, Manhattan, Kansas 66506 [W. M., M. S. C.], and Section of Medical Oncology, Department of Medicine, University of Oklahoma, Health Science Center, Oklahoma City, Oklahoma 73191 [D. S.]

Two human leukemia cell lines (Molt-4 and HL-60) have been used for establishing cells which exhibit a low level resistance to Adriamycin. Analysis of drug uptake patterns shows that the Molt-4 resistant cells are defective in the initial intracellular accumulation of drug. In contrast to Molt-4 the levels of drug which accumulate in the sensitive and resistant HL-60 cells during a 60-min incubation period are essentially the same. However, when incubations are continued there is a major reduction in intracellular drug levels in the resistant cell. Further studies show that resistant cells incubated in the presence of drug for extended time periods efflux drug at a rate considerably greater than that exhibited by the sensitive parent line. Similar efflux patterns are obtained with nuclei isolated from drug-sensitive and -resistant cells. Additional studies using an in vitro phosphorylation system demonstrate distinct protein changes in membranes of Molt-4 and HL-60 resistant cells. Thus, we have found that a membrane fraction from the Molt-4 resistant line contains a M_r 170,000 protein which is not detected in a similar fraction from cells sensitive to drug. HL-60 resistant membranes contain two proteins with molecular weights of 150,000 and 120,000 which are also not found in membranes from drug-sensitive cells. The results of this study suggest that drug resistance in HL-60 cells is related to an efflux mechanism which is triggered only after cells are exposed to drug for prolonged periods.

¹ This investigation was supported by Research Grant CA-37585 from the National Cancer Institute, Department of Health and Human Services.

² To whom requests for reprints should be addressed.

Received 1/ 8/86. Revised 4/18/86. Accepted 4/22/86.

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