title: Thalidomide enhances cyclophosphamide and dexamethasone-mediated cytotoxicity towards cultured chronic lymphocytic leukaemia cells.
abstract: 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 µM 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 µM 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.
authors.affiliation: Centre for Biomedical Research, University of Hull, Hull, HU6 7RX, USA.
authors.forename: Joanna C
authors.initials: JC
authors.lastname: Pointon
authors.forename: Gina
authors.initials: G
authors.lastname: Eagle
authors.forename: James
authors.initials: J
authors.lastname: Bailey
authors.forename: Paul
authors.initials: P
authors.lastname: Evans
authors.forename: David
authors.initials: D
authors.lastname: Allsup
authors.forename: John
authors.initials: J
authors.lastname: Greenman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015331:Cohort Studies; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology*; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D013792:Thalidomide / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D013792:Thalidomide; D003907:Dexamethasone; D003520:Cyclophosphamide