Reichle A, Diddens H, Altmayr F, Rastetter J, Andreesen R
Klinik und Poliklinik der Medizinischen Klinik I, Universität Regensburg, Germany.
Leuk Res. 1995 Nov;19(11):823-9. doi: 10.1016/0145-2126(95)00062-3.
Vincristine (VCR) accumulation in chronic lymphatic leukemia of B-cell origin (B-CLL) has recently been shown not to be inversely correlated to P-glycoprotein (PGP) levels. Therefore, we studied, in addition to PGP expression and accumulation of VCR, the cellular beta-tubulin content in quiescent and rhIL-2 activated B-CLL cells. VCR mediates cytotoxicity by binding to tubulin. Constitutive beta-tubulin levels in B-CLL cells varied considerably. Upon activation with rhIL-2, beta-tubulin expression increased significantly. Therefore, tubulin levels could be correlated over a wide range to VCR accumulation. When the PGP-mediated drug efflux was blocked by verapamil (VRP), tubulin levels correlated linearly to VCR accumulation. All B-CLL cases expressed PGP at different levels. There was no linear correlation between PGP expression and VCR accumulation. A modulation factor m was defined as a quotient of VCR accumulation in the presence and absence of VRP to define the extent by which VRP inhibited a steady-state accumulation of VCR. The factor allowed discrimination between B-CLLs expressing low versus high PGP, irrespective of the levels of tubulin. However, PGP and beta-tubulin levels together were predictive for VCR accumulation in steady state. There was no uniform-accumulation defect for VCR in B-cell CLL because beta-tubulin and PGP were expressed independently. Non PGP-mediated VCR transport seems to play a minor role in B-cell CLL. Leukemia-associated varying of cytoskeletal organization in B-cell CLL might be one reason for the diverse cellular responses to receptor-mediated signals.
最近研究表明，在B细胞来源的慢性淋巴细胞白血病（B-CLL）中，长春新碱（VCR）的蓄积与P-糖蛋白（PGP）水平并非呈负相关。因此，除了研究PGP表达和VCR蓄积外，我们还研究了静止和重组人白细胞介素-2（rhIL-2）激活的B-CLL细胞中的细胞β-微管蛋白含量。VCR通过与微管蛋白结合介导细胞毒性。B-CLL细胞中组成型β-微管蛋白水平差异很大。在用rhIL-2激活后，β-微管蛋白表达显著增加。因此，在很宽的范围内，微管蛋白水平与VCR蓄积相关。当用维拉帕米（VRP）阻断PGP介导的药物外排时，微管蛋白水平与VCR蓄积呈线性相关。所有B-CLL病例均表达不同水平的PGP。PGP表达与VCR蓄积之间无线性相关性。定义了一个调节因子m，作为存在和不存在VRP时VCR蓄积的商，以确定VRP抑制VCR稳态蓄积的程度。该因子可区分低PGP表达和高PGP表达的B-CLL，而与微管蛋白水平无关。然而，PGP和β-微管蛋白水平共同可预测稳态下VCR的蓄积。在B细胞CLL中，VCR不存在统一的蓄积缺陷，因为β-微管蛋白和PGP是独立表达的。非PGP介导的VCR转运在B细胞CLL中似乎起次要作用。B细胞CLL中白血病相关的细胞骨架组织变化可能是细胞对受体介导信号产生不同反应的原因之一。
