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Uptake and Intracellular Distribution of Doxorubicin Metabolites in B-Lymphocytes of Chronic Lymphocytic Leukemia¹

Divisions of Hematology and Oncology, Veterans Administration Medical Center and Vanderbilt University, Nashville, Tennessee 37203

The toxicity of doxorubicin metabolites was evaluated on lymphocytes of B-cell chronic lymphocytic leukemia. Only doxorubicinol was found to be cytotoxic for these lymphocytes, whereas exposure to aglycones at concentrations as high as 5 µM for 1 h had no effect on the proliferative capacity of these cells. After exposure of cells to isomolar concentrations of doxorubicin or its metabolites, uptake/retention of doxorubicinol was 23% of doxorubicin, and uptake/retention of aglycones was 5 to 13% of doxorubicin. Seventy to 90% of doxorubicin and 60 to 90% of doxorubicinol taken up/retained by the cells were detected in the cell nuclear fraction, whereas only 20 to 40% of the aglycones were localized in the cell nucleus. Cytotoxicity of metabolites was generally related to the proportion of drug taken up/retained by the cells and localized to the nuclei. The low uptake and nuclear localization may be at least partially responsible for the lack of cytotoxicity of aglycones on B-lymphocytes from chronic lymphocytic leukemia.

¹ Supported by the Veterans Administration and NIH Grants T32-AM07186 and BRSG-RR-05425.

² To whom requests for reprints should be addressed, at VA Medical Center, 1310 24th Avenue South, Nashville, TN 37203.

³ Present address: Roswell Park Memorial Institute, 666 Elm Street, Buffalo, NY 14263.

Received 5/19/86. Revised 10/ 9/87. Accepted 11/ 3/87.

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