In vitro activity of 20 agents in different prognostic subgroups of chronic lymphocytic leukemia – rolipram and prednisolone active in cells from patients with poor prognosis
Identifieur interne : 001864 ( Main/Exploration ); précédent : 001863; suivant : 001865In vitro activity of 20 agents in different prognostic subgroups of chronic lymphocytic leukemia – rolipram and prednisolone active in cells from patients with poor prognosis
Auteurs : Elin Lindhagen ; Maria Norberg ; Meena Kanduri ; Gerard Tobin ; Laura S Is Nen ; Magnus Berg ; Mats G. Gustafsson ; Christer Sundström ; Richard Rosenquist ; Anna Leskog [Suède]Source :
- European Journal of Haematology [ 0902-4441 ] ; 2009-07.
English descriptors
- Teeft :
- Aberration, Acute lymphoblastic leukemia, Additivity, Alkylating regimens, Amersham biosciences, Anticancer drugs, Antileukemic activity, Antileukemic agents, Apoptosis, Assay, Beckman coulter, Binet stage, Black line, Cell lines, Cell lysates, Cell survival, Chlorambucil, Clin cancer, Clinical data, Clinical experience, Clinical pharmacology, Clinical resistance, Clinical studies, Colon, Colon cancer, Combination experiments, Complete data, Control wells, Conventional therapy, Current study, Cytotoxic, Cytotoxicity, Different genomic aberrations, Different prognostic subgroups, Drug concentration, Drug resistance, Drug sensitivity, Error bars, Expression levels, Further studies, Gene expression, Gene expression analysis, Genomic, Genomic aberrations, Glucocorticoid, Glucocorticoid pathway, Glucocorticoid receptor, Glucocorticoid resistance, Grey line, Healthy donors, Healthy volunteers, High activity, Higher activity, Higher sensitivity, Ighv, Ighv genes, Ighv mutation status, Immunoblot analysis, Immunoglobulin heavychain, Inconclusive data, Individual patient samples, Inferior prognosis, Inhibitor, Inhibitor rolipram, Interaction index, John wiley sons, John wiley sons drug sensitivity, John wiley sons lindhagen, Leukemia, Lindhagen, Loewe, Loewe additivity, Lower response, Lymphocytic leukemia, Lymphoid cells, Mammary adenocarcinoma, Maximum effect, Median, Median survival, Median time, Medical sciences, Methyl prednisolone, Microtitre plates, Mutation, Mutational status, Nfjb activation, Normal lymphocytes, Ovarian cancer, Overall survival, Pathway, Patient tumor cells, Pbmc, Peripheral blood, Phosphodiesterase, Poor prognosis, Poor response, Positive interaction index, Prednisolone, Prednisolone rolipram, Primary tumor cells, Prognostic, Prognostic markers, Protein kinase, Purine analogues, Receptor, Resistant cases, Rolipram, Sensitive cases, Sensitivity differences, Side effects, Subgroup, Tumor cell, Tumor cells, Udarabine, Umcll samples, Unmutated, Unmutated ighv genes, Untreated patients, Uorometric microculture cytotoxicity assay, Uppsala, Uppsala university hospital.
Abstract
Background: 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 antileukemic activity of 20 different anticancer agents was characterized in tumor cells from CLL, aiming at identifying agents active in poor‐prognostic subgroups. Design and methods: In tumor cells from 40 CLL patients and in peripheral blood mononuclear cells (PBMC) from three healthy controls, the activity of 20 substances was assessed using a non‐clonogenic assay. The CLL samples were characterized regarding genomic aberrations by interphase fluorescence in situ hybridization and immunoglobulin heavy‐chain variable (IGHV) gene mutational status. Results: 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 vs. 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 signaling. Conclusion: 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.
Url:
DOI: 10.1111/j.1600-0609.2009.01248.x
Affiliations:
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University</wicri:regionArea><placeName><settlement type="city">Uppsala</settlement><region nuts="1">Svealand</region><region nuts="1">East Middle Sweden</region></placeName><orgName type="university">Université d'Uppsala</orgName></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">European Journal of Haematology</title><title level="j" type="alt">EUROPEAN JOURNAL OF HAEMATOLOGY</title><idno type="ISSN">0902-4441</idno><idno type="eISSN">1600-0609</idno><imprint><biblScope unit="vol">83</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="22">22</biblScope><biblScope unit="page" to="34">34</biblScope><biblScope unit="page-count">13</biblScope><publisher>Blackwell Publishing Ltd</publisher><pubPlace>Oxford, UK</pubPlace><date type="published" when="2009-07">2009-07</date></imprint><idno type="ISSN">0902-4441</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0902-4441</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="Teeft" xml:lang="en"><term>Aberration</term><term>Acute lymphoblastic leukemia</term><term>Additivity</term><term>Alkylating regimens</term><term>Amersham biosciences</term><term>Anticancer drugs</term><term>Antileukemic activity</term><term>Antileukemic agents</term><term>Apoptosis</term><term>Assay</term><term>Beckman coulter</term><term>Binet stage</term><term>Black line</term><term>Cell lines</term><term>Cell lysates</term><term>Cell survival</term><term>Chlorambucil</term><term>Clin cancer</term><term>Clinical data</term><term>Clinical experience</term><term>Clinical pharmacology</term><term>Clinical resistance</term><term>Clinical studies</term><term>Colon</term><term>Colon cancer</term><term>Combination experiments</term><term>Complete data</term><term>Control wells</term><term>Conventional therapy</term><term>Current study</term><term>Cytotoxic</term><term>Cytotoxicity</term><term>Different genomic aberrations</term><term>Different prognostic subgroups</term><term>Drug concentration</term><term>Drug resistance</term><term>Drug sensitivity</term><term>Error bars</term><term>Expression levels</term><term>Further studies</term><term>Gene expression</term><term>Gene expression analysis</term><term>Genomic</term><term>Genomic aberrations</term><term>Glucocorticoid</term><term>Glucocorticoid pathway</term><term>Glucocorticoid receptor</term><term>Glucocorticoid resistance</term><term>Grey line</term><term>Healthy donors</term><term>Healthy volunteers</term><term>High activity</term><term>Higher activity</term><term>Higher sensitivity</term><term>Ighv</term><term>Ighv genes</term><term>Ighv mutation status</term><term>Immunoblot analysis</term><term>Immunoglobulin heavychain</term><term>Inconclusive data</term><term>Individual patient samples</term><term>Inferior prognosis</term><term>Inhibitor</term><term>Inhibitor rolipram</term><term>Interaction index</term><term>John wiley sons</term><term>John wiley sons drug sensitivity</term><term>John wiley sons lindhagen</term><term>Leukemia</term><term>Lindhagen</term><term>Loewe</term><term>Loewe additivity</term><term>Lower response</term><term>Lymphocytic leukemia</term><term>Lymphoid cells</term><term>Mammary adenocarcinoma</term><term>Maximum effect</term><term>Median</term><term>Median survival</term><term>Median time</term><term>Medical sciences</term><term>Methyl prednisolone</term><term>Microtitre plates</term><term>Mutation</term><term>Mutational status</term><term>Nfjb activation</term><term>Normal lymphocytes</term><term>Ovarian cancer</term><term>Overall survival</term><term>Pathway</term><term>Patient tumor cells</term><term>Pbmc</term><term>Peripheral blood</term><term>Phosphodiesterase</term><term>Poor prognosis</term><term>Poor response</term><term>Positive interaction index</term><term>Prednisolone</term><term>Prednisolone rolipram</term><term>Primary tumor cells</term><term>Prognostic</term><term>Prognostic markers</term><term>Protein kinase</term><term>Purine analogues</term><term>Receptor</term><term>Resistant cases</term><term>Rolipram</term><term>Sensitive cases</term><term>Sensitivity differences</term><term>Side effects</term><term>Subgroup</term><term>Tumor cell</term><term>Tumor cells</term><term>Udarabine</term><term>Umcll samples</term><term>Unmutated</term><term>Unmutated ighv genes</term><term>Untreated patients</term><term>Uorometric microculture cytotoxicity assay</term><term>Uppsala</term><term>Uppsala university hospital</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Background: 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 antileukemic activity of 20 different anticancer agents was characterized in tumor cells from CLL, aiming at identifying agents active in poor‐prognostic subgroups. Design and methods: In tumor cells from 40 CLL patients and in peripheral blood mononuclear cells (PBMC) from three healthy controls, the activity of 20 substances was assessed using a non‐clonogenic assay. The CLL samples were characterized regarding genomic aberrations by interphase fluorescence in situ hybridization and immunoglobulin heavy‐chain variable (IGHV) gene mutational status. Results: 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 vs. 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 signaling. Conclusion: 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.</div></front></TEI><affiliations><list><country><li>Suède</li></country><region><li>East Middle Sweden</li><li>Svealand</li></region><settlement><li>Uppsala</li></settlement><orgName><li>Université d'Uppsala</li></orgName></list><tree><noCountry><name sortKey=" Berg, Magnus" sort=" Berg, Magnus" uniqKey=" Berg M" first="Magnus" last=" Berg">Magnus Berg</name><name sortKey="Gustafsson, Mats G" sort="Gustafsson, Mats G" uniqKey="Gustafsson M" first="Mats G." last="Gustafsson">Mats G. Gustafsson</name><name sortKey="Kanduri, Meena" sort="Kanduri, Meena" uniqKey="Kanduri M" first="Meena" last="Kanduri">Meena Kanduri</name><name sortKey="Lindhagen, Elin" sort="Lindhagen, Elin" uniqKey="Lindhagen E" first="Elin" last="Lindhagen">Elin Lindhagen</name><name sortKey="Norberg, Maria" sort="Norberg, Maria" uniqKey="Norberg M" first="Maria" last="Norberg">Maria Norberg</name><name sortKey="Rosenquist, Richard" sort="Rosenquist, Richard" uniqKey="Rosenquist R" first="Richard" last="Rosenquist">Richard Rosenquist</name><name sortKey="S Is Nen, Laura" sort="S Is Nen, Laura" uniqKey="S Is Nen L" first="Laura" last="S Is Nen">Laura S Is Nen</name><name sortKey="Sundstrom, Christer" sort="Sundstrom, Christer" uniqKey="Sundstrom C" first="Christer" last="Sundström">Christer Sundström</name><name sortKey="Tobin, Gerard" sort="Tobin, Gerard" uniqKey="Tobin G" first="Gerard" last="Tobin">Gerard Tobin</name></noCountry><country name="Suède"><region name="Svealand"><name sortKey=" Leskog, Anna" sort=" Leskog, Anna" uniqKey=" Leskog A" first="Anna" last=" Leskog">Anna Leskog</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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