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

نویسندگان

  • A Reichle
  • H Diddens
  • F Altmayr
  • J Rastetter
  • R Andreesen
چکیده

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.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Revisiting Beta 2 Glycoprotein I, the Major Autoantigen in the Antiphospholipid Syndrome

Beta 2 glycoprotein I (β2GPI) is a single chain 50 kDa highly glycosylated glycoprotein at an approximate concentration of 4 μM in cells. The abundance of this protein in plasma and its high state of preservation indicate the important role of this protein in mammalian. In addition, β2GPI has a particular structure in the fifth domain, and is categorized as the major antigen recognized by autoa...

متن کامل

Evaluating the Effects of Cytomegalovirus Glycoprotein B on the Maturation and Function of Monocyte-derived dendritic cells

Background & Objectives: Interaction of cytomegalovirus glycoprotein B with toll-like receptors of dendritic cells leads to early signaling and innate immune responses. The aim of this study is to evaluate the effects of cytomegalovirus glycoprotein B on the maturation and function of monocyte-derived dendritic cells in treated groups in comparison with control groups. Materials & Methods: Bloo...

متن کامل

Cells resistant to HTI-286 do not overexpress P-glycoprotein but have reduced drug accumulation and a point mutation in alpha-tubulin.

HTI-286, a synthetic analogue of hemiasterlin, depolymerizes microtubules and is proposed to bind at the Vinca peptide site in tubulin. It has excellent in vivo antitumor activity in human xenograft models, including tumors that express P-glycoprotein, and is in phase II clinical evaluation. To identify potential mechanisms of resistance induced by HTI-286, KB-3-1 epidermoid carcinoma cells wer...

متن کامل

Chronic lymphocytic leukemia, biology, new diagnosis and treatment: review article

Chronic lymphocytic leukemia (CLL) is a malignancy of B CD5+cells and is the most common type of leukemia in adults. The disease is more common in men over 50 years in western countries. CLL is associated with defective apoptosis in B cells. CLL was traditionally regarded as a disease that occurs before naïve B cells meet the antigen in the lymph nodes. Laboratory diagnosis requires white blood...

متن کامل

ایمونوفنوتایپینگ بیماران مبتلا به لوسمی لنفوسیتی مزمن (CLL) به روش فلوسیتومتری؛ ارتباط با پیش آگهی بیماری

Background and purpose: Chronic lymphocytic leukemia (CLL) is characterized by clonal proliferation and accumulation of long-lived B lymphocytes within the peripheral blood, bone marrow, and secondary lymphoid organs. In this study, immunophenotypic characteristics of leukemic cells and their association with disease prognosis were investigated in CLL patients. Materials and methods: A case-...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:
  • Leukemia research

دوره 19 11  شماره 

صفحات  -

تاریخ انتشار 1995