Beta-tubulin and P-glycoprotein: Major determinants of vincristine accumulation in B-CLL cells

• Published in: Leukemia research Vol. 19; no. 11; pp. 823 - 829
• Main Authors: Reichle, A., Diddens, H., Altmayr, F., Rastetter, J., Andreesen, R.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.11.1995; Elsevier Science
• Subjects: Aged; Aged, 80 and over; Antineoplastic agents; Antineoplastic Agents, Phytogenic - pharmacokinetics; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; B-CLL; Biological and medical sciences; Blotting, Northern; Calcium Channel Blockers - pharmacology; Female; General aspects; Humans; Immunophenotyping; Interleukin-2 - pharmacology; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Male; Medical sciences; Middle Aged; Multidrug resistance; Pharmacology. Drug treatments; Recombinant Proteins - pharmacology; tubulin; Tubulin - metabolism; Tumor Cells, Cultured - metabolism; Verapamil - pharmacology; vincristine; Vincristine - pharmacokinetics; tubulin; vincristine; Multidrug resistance; B-CLL; Antineoplastic agent; Human; Beta-Peptide chain; P Glycoprotein; Contractile protein; Malignant hemopathy; B-Lymphocyte; Alkaloid; Chronic; Chronic lymphocytic leukemia; Tubulin; Lymphoproliferative syndrome; Multiple resistance; Biological accumulation; Negative therapeutic reaction
• ISSN: 0145-2126; 1873-5835
• 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 β-tubulin content in quiescent and rhIL-2 activated B-CLL cells. VCR mediates cytotoxicity by binding to tubulin. Constitutive β-tubulin levels in B-CLL cells varied considerably. Upon activation with rhIL-2, β-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 β-tubulin levels together were predictive for VCR accumulation in steady state. There was no uniform accumulation defect for VCR in B-cell CLL because β-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.