Haber M, Norris M D, Kavallaris M, Bell D R, Davey R A, White L, Stewart B W
Children's Leukaemia and Cancer Research Unit, Prince of Wales Children's Hospital, Randwick, Sydney, New South Wales, Australia.
Cancer Res. 1989 Oct 1;49(19):5281-7.
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.
近乎二倍体的白血病 T 细胞（LALW - 2），仅因供体患者接受治疗而接触细胞毒性药物，通过在裸鼠中的连续异种移植得以维持。与白血病细胞系 CCRF - CEM 相比，采用生长抑制试验，LALW - 2 细胞对长春花生物碱和放线菌素 D 具有抗性（相对抗性为 200 倍或更高），对阿霉素有轻微抗性（相对抗性为 4 倍），而对柔红霉素或替尼泊苷无抗性。相比之下，我们实验室培育的长春新碱抗性 CEM 亚系（CEM/VCR R）对所有这些药物的抗性至少为 30 倍。VCR R 亚系用作阳性对照，证实了先前报道的多药抗性与 P - 糖蛋白基因扩增之间的相关性。对 CEM、CEM/VCR R 和 LALW - 2 细胞的比较表明，P - 糖蛋白基因在 LALW - 2 细胞中未扩增或过表达；在这些细胞的提取物中通过免疫印迹也检测不到该基因产物。LALW - 2 细胞与 CEM/VCR R 细胞的进一步区别在于，异种移植细胞的长春新碱外排未增加，而这一效应在 CEM/VCR R 细胞中很容易得到证实。然而，尽管 LALW - 2 细胞外排长春新碱的速率与 CCRF - CEM 细胞相同，但异种移植细胞的长春新碱积累速率降低。LALW - 2 细胞对柔红霉素的摄取与 CEM 细胞无异，这与两种细胞群体中该药物相似的 50%抑制剂量水平一致，且与 CEM/VCR R 细胞不同。因此，在这种情况下的临床抗性似乎是一种“非典型”的多药抗性形式，其具体特征是在没有 P - 糖蛋白增加量的情况下对长春花生物碱和放线菌素 D 具有抗性，并且表现为药物摄取减少。
