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Rapamycin shows anticancer activity in primary chronic lymphocytic leukemia cells in vitro, as single agent and in drug combination
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Blodsjukdomar)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. (Rosenquist Brandell)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Onkologisk farmakologi o informatik)
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2008 (English)In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 49, no 12, 2333-2343 p.Article in journal (Refereed) Published
Abstract [en]

The mammalian target of rapamycin inhibitor rapamycin and its analogues show promising anticancer activity in various experimental tumor models and are presently evaluated in clinical trials. We, here, evaluated the in vitro activity of rapamycin with regard to tumor-type specificity and possible mechanisms of drug resistance in 97 tumor cell samples from patients and in a resistance-based cell line panel, using the fluorometric microculture cytotoxicity assay. Rapamycin was dose-dependently cytotoxic in patient tumor cells and in cell lines. In primary cells, rapamycin was more active in hematological than in solid tumor samples, with chronic lymphocytic leukemia (CLL) and acute lymphocytic leukemia being the most sensitive tumor types. Considerable inter-individual differences in sensitivity were apparent among CLL samples, but no difference was observed between IGHV mutated and unmutated CLL samples, whereas a tendency to lower rapamycin sensitivity was indicated for samples displaying poor-prognostic genomic markers. Combination experiments in CLL cells indicated that rapamycin acted synergistically with vincristine, cisplatin, chlorambucil and taxotere. These results and the clinically-experienced good tolerance to rapamycin analogues encourage clinical studies of rapamycin in CLL treatment as single agent but also in combination with, e.g., vincristine and chlorambucil.

Place, publisher, year, edition, pages
2008. Vol. 49, no 12, 2333-2343 p.
Keyword [en]
mTOR inhibitor, rapamycin, cytotoxicity, primary tumor samples, chronic lymphocytic leukemia, synergistic activity
National Category
Medical and Health Sciences Engineering and Technology
Research subject
Signal Processing
Identifiers
URN: urn:nbn:se:uu:diva-111058DOI: 10.1080/10428190802475295ISI: 000261734200019PubMedID: 19052982OAI: oai:DiVA.org:uu-111058DiVA: diva2:279253
Available from: 2009-12-02 Created: 2009-12-02 Last updated: 2017-12-12Bibliographically 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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 537
Keyword
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
Identifiers
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)
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Supervisors
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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