Thalidomide enhances cyclophosphamide and dexamethasone-mediated cytotoxicity towards cultured chronic lymphocytic leukaemia cells.

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BlankThalidomide enhances cyclophosphamide and dexamethasone-mediated

cytotoxicity towards cultured chronic lymphocytic leukaemia cells.

JC Pointon, G Eagle, J , P , D Allsup, and J Greenman

Oncol Rep, November 1, 2010; 24(5): 1315-21.

Centre for Biomedical Research, University of Hull, Hull, HU6 7RX, USA.

Numerous chemotherapeutic regimens exist for the treatment of symptomatic or

progressive chronic lymphocytic leukaemia (CLL). However, once the disease

becomes refractory to nucleoside-based therapy the prognosis is poor. In this

study we investigated the cytotoxicity of thalidomide in combination with

dexamethasone, fludarabine and cyclophosphamide. Cells from a cohort of 25 CLL

patients were incubated for 72 h with each of these three agents, at 3

concentrations, both with and without thalidomide. Cell viability was assessed

using the Annexin V:FITC assay. Fludarabine was highly toxic to the cells,

producing very high levels of cell death; however, thalidomide did not increase

this effect. Cyclophosphamide combined with thalidomide showed a small,

non-significant improvement in toxicity compared with monotherapy. Median cell

death for 5 ?M dexamethasone monotherapy and for combination with thalidomide

was 15% [interquartile range (IQR) 0-38%] and 17% (IQR 0-54%), respectively

(Wilcoxon Signed Rank analysis, p=0.034). Cell death for 10 ?M dexamethasone

monotherapy was 15% (IQR 0-45%) and 16% (IQR 0-62%) in combination with

thalidomide (Wilcoxon Signed Rank analysis, p=0.035). At the highest doses

tested 11 of 25 cases displayed an enhancement of cyclophosphamide-mediated

cytotoxicity, and 14 of 25 cases showed enhanced dexamethasone-mediated

cytotoxicity in the presence of thalidomide. Some CLL cells in which

dexamethasone-mediated killing was enhanced were derived from patients with poor

prognostic markers, including p53 mutations and unmutated IgVH genes. In

summary, thalidomide enhances cyclophosphamide- and dexamethasone-mediated

cytotoxicity of CLL cells in vitro in a proportion of cases.

PMID: 20878126