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Reversal of Acquired Resistance to Doxorubicin in P388 Murine Leukemia Cells by Perhexiline Maleate¹

Department of Radiation and Clinical Oncology, Hadassah University Hospital, P. O. Box 12000, Jerusalem, Israel 91120 [A. R., Z. F.]; Laboratory of Neurochemistry, Department of Biochemistry, The Hebrew University-Hadassah Medical School, Jerusalem, Israel 91010 [S. G.]; and Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20205 [D. G.]

The effects of perhexiline maleate on growth and drug sensitivity were studied in the P388 murine leukemia cell line and in an anthracycline-resistant subline (P388/ADR). At noninhibitory concentrations, perhexiline maleate markedly increased the sensitivity of P388/ADR cells to doxorubicin but did not have such an effect on anthracycline-sensitive cells.

The effects of perhexiline maleate on P388/ADR cells were reversible. Perhexiline maleate also increased the accumulation of another anthracycline, daunorubicin, in P388/ADR cells but did not increase its accumulation in the anthracycline-sensitive cells.

Perhexiline maleate did not affect the sensitivity of either cell line to methotrexate or to 6-mercaptopurine. However, its effects on the sensitivity and on drug accumulation of vinblastine, a drug to which P388/ADR cells are cross-resistant, were similar to those observed for the anthracyclines.

Although perhexiline maleate has been reported to be a calcium antagonist in other systems, our data do not suggest that this mechanism is involved in its enhancement of the sensitivity of P388/ADR cells to doxorubicin. We suggest instead that this effect might be associated with alterations of cell lipid metabolism induced by perhexiline maleate.

¹ This work was supported by grants from the Joint Research Fund of the Hebrew University and Hadassah and from the Israel Cancer Research Fund.

² To whom requests for reprints should be addressed.

Received 3/25/83. Accepted 10/ 3/83.