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.