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Atypical Multidrug Resistance in a Therapy-induced Drug-resistant Human Leukemia Cell Line (LALW-2): Resistance to Vinca Alkaloids Independent of P-Glycoprotein¹

Children's Leukaemia and Cancer Research Unit, Prince of Wales Children's Hospital, High Street, Randwick, Sydney, New South Wales, 2031 [M. H., M. D. N., M. K., L. W., B. W. S.]; School of Paediatrics, University of New South Wales, P. O. Box 1, Kensington, Sydney, New South Wales, 2033 [L. W., B. W. S.]; and Department of Clinical Oncology, Royal North Shore Hospital, Pacific Highway, St. Leonards, Sydney, New South Wales 2065 [D. R. B., R. A. D.], Australia

Near diploid leukemic T-cells (LALW-2), exposed to cytotoxic drugs only as a consequence of therapy administered to the donor patient, have been maintained by serial xenograft in nude mice. In comparison with the leukemic line CCRF-CEM, using a growth inhibition assay, LALW-2 cells were resistant to Vinca alkaloids and actinomycin D (relative resistance, 200-fold or more), were slightly resistant to Adriamycin (relative resistance, 4-fold), and showed no resistance to daunorubicin or teniposide. By comparison, a vincristine-resistant CEM subline developed in our laboratory (CEM/VCR R) was resistant to all these agents by at least 30-fold. The VCR R subline served as a positive control, confirming the previously reported correlation between multidrug resistance and amplification of the P-glycoprotein gene. Comparison of CEM, CEM/VCR R, and LALW-2 cells establish that the P-glycoprotein gene was not amplified or overexpressed in the LALW-2 cells; neither could the gene product be detected by immunoblotting in extracts from these cells. The LALW-2 cells were further distinguished from CEM/VCR R cells due to the lack of increased vincristine efflux by the xenografted cells, an effect readily demonstrable in the CEM/VCR R cells. However, although LALW-2 cells efflux vincristine at the same rate as CCRF-CEM cells, the xenografted cells exhibited a reduced rate of vincristine accumulation. Uptake of daunorubicin by LALW-2 cells was not distinguished from that by CEM cells, consistent with similar 50% inhibitory dose levels for this drug in both cell populations, and differentiating both from CEM/VCR R cells. Thus, clinical resistance in this case appears to be an "atypical" form of multidrug resistance specifically distinguished by resistance to Vinca alkaloids and actinomycin D occurring in the absence of increased amounts of P-glycoprotein and manifesting decreased drug uptake.

¹ This investigation was supported by the Children's Leukaemia and Cancer Foundation (Australia) and also by a grant from the National Health and Medical Research Council (Australia).

All procedures involving experimental animals were carried out in accordance with permits issued by the Committee on the Use of Animals in Research or Teaching of the University of New South Wales and in accordance with Guidelines for the Care and Use of Animals for Experimental Purposes issued by the National Health and Medical Research Council (Australia).

² To whom requests for reprints should be addressed, at Children's Leukaemia and Cancer Research Unit, Prince of Wales Children's Hospital, High Street, Randwick, New South Wales, 2031, Australia.

Received 10/17/88. Revised 4/28/89. Accepted 6/27/89.

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