In vitro activity of 20 agents in different prognostic subgroups of chronic lymphocytic leukaemia: rolipram and prednisolone active in cells from patients with poor prognosis
2009 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 83, no 1, 22-34 p.Article in journal (Refereed) Published
There is a need for development of new drugs for treatment of B-cell chronic lymphocytic leukemia (CLL), especially for poor-prognostic subgroups resistant to conventional therapy. Objective: The in vitro antileukaemic activity of 20 different anticancer agents was characterized in tumour cells from CLL, aiming at identifying agents active in poor-prognostic subgroups.
Design and methods:
In tumour cells from 40 CLL patients and in peripheral blood mononuclear cells (PBMC) from 3 healthy controls, the activity of 20 substances was assessed using a non-clonogenic assay. The CLL samples were characterized regarding genomic aberrations by interphase FISH and immunoglobulin heavy-chain variable (IGHV) gene mutational status.
In line with clinical experience, cells from patients with unfavourable genomic aberrations (del(11q)/del(17p)) showed lower drug sensitivity to fludarabine and chlorambucil than cells from patients with favourable cytogenetics (del(13q)/no aberration). Most investigated drugs demonstrated similar activity in CLL cells from patients with unmutated and mutated IGHV genes as well as in CLL cells versus PBMC. Interestingly, prednisolone and rolipram displayed high CLL specificity, high activity in CLL cells with unmutated IGHV genes and retained the effect in several cases with 11q/17p deletion. Further studies on prednisolone and rolipram revealed a synergy when these agents were combined in CLL cells, and suggested correlation between drug sensitivity and difference in downstream signalling.
Prednisolone and rolipram are interesting for further studies in CLL with inferior prognosis. The study can also be considered a basis for future efforts to find drugs active in subsets of CLL patients that are resistant to conventional therapy.
Place, publisher, year, edition, pages
2009. Vol. 83, no 1, 22-34 p.
chronic lymphocytic leukemia, cellular drug sensitivity, IGHV mutation status, genomic aberrations, rolipram, prednisolone
Medical and Health Sciences Engineering and Technology
IdentifiersURN: urn:nbn:se:uu:diva-102362DOI: 10.1111/j.1600-0609.2009.01248.xISI: 000266875000003PubMedID: 19245531OAI: oai:DiVA.org:uu-102362DiVA: diva2:214786