Atypical multidrug resistance in a therapy-induced drug-resistant human leukemia cell line (LALW-2): resistance to Vinca alkaloids independent of P-glycoprotein.
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.
Haber
M
M
Children's Leukaemia and Cancer Research Unit, Prince of Wales Children's Hospital, Randwick, Sydney, New South Wales, Australia.
Norris
M D
MD
Kavallaris
M
M
Bell
D R
DR
Davey
R A
RA
White
L
L
Stewart
B W
BW
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D003630:Daunorubicin / Q000378:metabolism; D004351:Drug Resistance; D005784:Gene Amplification; D006801:Humans; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism*; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000378:metabolism; D014748:Vinca Alkaloids / Q000378:metabolism*; D014750:Vincristine / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008562:Membrane Glycoproteins; D014748:Vinca Alkaloids; D014750:Vincristine; D003630:Daunorubicin