Selective toxicity of vincristine against chronic lymphocytic leukemia cells in vitro

Abstract

The cytotoxicity of vincristine in vitro was investigated in B chronic lymphocytic leukemia (CLL) cells and in normal peripheral blood mononuclear cells. An approximately 25-fold selectivity towards leukemic vs. normal lymphocytes was demonstrated. Cells from patients having a mature subtype (CLL or CLL/mix) or a slowly progressing form of CLL were significantly more sensitive to vincristine in vitro than the cases with a CLL/PL phenotype or faster-progressing disease. Depending on the vincristine dose, the number of dead CLL cells accumulated slowly during the 4-d observation period. Our data indicate a marked individual variation in vincristine susceptibility among individual CLL cells. Vincristine induced annexin positivity, nuclear blebbing and DNA fragmentation in CLL cells. These indicate an "apoptosis-like" cell death. Since CLL cells are in the G0/G1 phase of the cell cycle, the only known mode of anticancer action of vinca alkaloids, i.e. anti-mitotic action, cannot explain the death of CLL cells. Furthermore, similar cellular uptake and efflux of vincristine by normal and CLL cells excluded pharmacokinetic differences as a cause of selectivity of vincristine towards leukemic lymphocytes. Immunostaining of filamentous structures of CLL cells revealed that vincristine brings about selective changes in alpha-tubulin but not in beta-actin or vimentin. Although the antitubulin action of vinca alkaloids in the biochemical sense is well demonstrated, this kind of anticancer effect has not previously been shown. Vincristine is used in several regimens for CLL, but its efficacy in CLL has never been demonstrated in a clinical context and its value in routine CLL chemotherapy has been questioned. The present data strongly support the need for further evaluation of the role and mode of action of vincristine in chemotherapy of CLL and other cancers as well.

Rapid induction of apoptosis in chronic lymphocytic leukemia cells by the microtubule disrupting agent BNC105

“…Microtubule-targeting agents have been classified as "mitosis-targeting agents," and yet they are effective against human tumors that are in interphase. [15][16][17] Our work with microtubule destabilizing agents (vinca alkaloids, CA4, BNC105) supports the theory that mitosis is not the sole or even major target for their drug cytotoxicity in haematopoietic malignancies. Microtubules organize the cytoskeleton during interphase and are essential for cellular trafficking.…”

Toll-like Receptor-7 Tolerizes Malignant B Cells and Enhances Killing by Cytotoxic Agents

“…Because, in retrospect, these cells had been tolerized, we considered that their sensitivity to CTLs might extend to cytotoxic drugs. Vincristine is a microtubule inhibitor with activity against CLL cells in vitro (24). A dose of 0.1 Ag/mL of vincristine was found to be relatively nontoxic to CLL cells (shown in Fig.…”

Surface antigen expression in chronic lymphocytic leukemia: clustering analysis, interrelationships and effects of chromosomal abnormalities

“…Peripheral blood leukemic cells were isolated using traditional methods as described. 11,12 The proportion of monocytes plus polyclonal T-and B-lymphocytes was 1-13%, indicating that 87-99% of the isolated cells represented the leukemic population (for details of the immunophenotyping, see below).…”