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.
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.


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.


CONCLUSIONS
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.
Lindhagen
Elin
E
Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Norberg
Maria
M
Kanduri
Meena
M
Tobin
Gerard
G
Säisänen
Laura
L
Aberg
Magnus
M
Gustafsson
Mats G
MG
Sundström
Christer
C
Rosenquist
Richard
R
Aleskog
Anna
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016022:Case-Control Studies; D002872:Chromosome Deletion; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D005260:Female; D050438:Genes, Immunoglobulin Heavy Chain; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D066298:In Vitro Techniques; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000145:classification / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011239:Prednisolone / Q000494:pharmacology*; D011379:Prognosis; D011965:Receptors, Glucocorticoid / Q000235:genetics; D020889:Rolipram / Q000494:pharmacology*; D014314:Trisomy
D000970:Antineoplastic Agents; D011965:Receptors, Glucocorticoid; D011239:Prednisolone; D020889:Rolipram