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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
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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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
Abstract [en]


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.
Keyword [en]
chronic lymphocytic leukemia, cellular drug sensitivity, IGHV mutation status, genomic aberrations, rolipram, prednisolone
National Category
Medical and Health Sciences Engineering and Technology
URN: urn:nbn:se:uu:diva-102362DOI: 10.1111/j.1600-0609.2009.01248.xISI: 000266875000003PubMedID: 19245531OAI: oai:DiVA.org:uu-102362DiVA: diva2:214786
Available from: 2009-05-06 Created: 2009-05-06 Last updated: 2016-04-14Bibliographically approved
In thesis
1. In Vitro Drug Sensitivity and Apoptosis in Chronic Lymphocytic Leukemia
Open this publication in new window or tab >>In Vitro Drug Sensitivity and Apoptosis in Chronic Lymphocytic Leukemia
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chronic lymphocytic leukemia (CLL) is a heterogeneous malignancy displaying varying clinical outcome, where molecular markers today can divide patients into prognostic subgroups. Despite the introduction of new agents for treatment, remissions are usually not sustained in CLL and resistance towards treatment can partly be explained by aberrant apoptosis. The aim of this thesis was to find new drugs for CLL patients resistant to conventional therapy and to analyze genes involved in apoptosis within different prognostic subgroups.

In paper I-II, the in vitro activity of substances was investigated using the fluorometric microculture cytotoxicity assay (FMCA). When evaluating rapamycin (paper I), an inhibitor of mTOR, in 97 tumor samples from different entities, CLL was found to be one of the most sensitive tumor types. Combination experiments on patient CLL cells indicated that rapamycin acted synergistically with the CLL drugs vincristine and chlorambucil.

An investigation of 20 anti-cancer agents in cells from 40 CLL patients (paper II) revealed that prednisolone and rolipram displayed high activity in poor-prognostic patients, in particular IGHV unmutated CLL. Furthermore, when used in combination these agents were found to produce a synergistic effect.

In paper III, the anti-apoptotic BCL2 family member BFL1 was evaluated in 37 CLL cases. Levels of BFL1 were higher in fludarabine-resistant patients compared to fludarabine-sensitive patients. In addition, the high expression of BFL1 inversely correlated to fludarabine-induced apoptosis in CLL cells.

A single nucleotide polymorphism in the anti-apoptotic BCL2 gene (-938C>A) has been suggested as a novel poor-prognostic marker in CLL. In paper IV, we investigated this BCL2 polymorphism in 268 CLL patients and correlated genotypes to clinical data. However, no association could be confirmed between this polymorphism and clinical outcome or established prognostic markers.

In conclusion, this thesis has shown that rapamycin is a potential drug for treatment in CLL. Furthermore, prednisolone and rolipram were identified as interesting candidates for treatment of poor-prognostic patients. Finally, the anti-apoptotic protein BFL1 may contribute to chemoresistance and hence represents a potential therapeutic target in CLL, whereas from our data, the BCL2 -938C>A polymorphism does not appear to have any prognostic significance.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 74 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 537
chronic lymphocytic leukemia, in vitro drug sensitivity, apoptosis, prognostic markers
National Category
Medical Genetics Hematology Medical Genetics Medical and Health Sciences Medical Genetics
Research subject
Medical Science; Clinical Genetics; Molecular Genetics; Medical Genetics; Molecular Medicine
urn:nbn:se:uu:diva-120299 (URN)978-91-554-7750-9 (ISBN)
Public defence
2010-04-29, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 09:00 (English)
Available from: 2010-04-07 Created: 2010-03-11 Last updated: 2010-04-07Bibliographically approved

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Gustafsson, Mats G.
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Clinical PharmacologyDepartment of Genetics and PathologyDepartment of Medical SciencesSignals and Systems Group
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