title: Can ex vivo evaluation (testing) predict the sensitivity of CLL cells to therapy with purine analogs in conjunction with an alkylating agent? A comparison of in vivo and ex vivo responses to treatment.
abstract: Malfunctions in the regulation of apoptosis cause the accumulation of malignant, long-lived B CD19+/CD5+ cells in chronic lymphocytic leukemia (CLL). The primary goal in CLL therapy is to overcome resistance to apoptosis and efficiently trigger programmed cell death in leukemic cells. This study demonstrated that the in vivo responses of malignant cells from CLL patients after administration of purine analogs (cladribine/fludarabine) with cyclophosphamide vary significantly. For comparative purposes, the sensitivity of leukemic cells obtained from the same CLL patients to conventional purine analogs and the selective CDK inhibitor R-roscovitine (ROSC) was determined, with and without the addition of an alkylating agent, prior to the onset of in vivo therapy. The kinetics and rate of spontaneous and drug-induced apoptosis of CLL cells under ex vivo conditions differed significantly between patients, mirroring the variability observed during in vivo treatment. Interestingly, individual patients' leukemic cells were comparably sensitive to the drugs under both conditions. Of the drugs examined, ROSC exerted the highest therapeutic efficacy under ex vivo conditions. Our results indicate that ex vivo testing might be useful for identifying the most potent first-line therapeutic regimen for specific CLL patients and possibly for the design of therapies tailored for individual CLL patients.
authors.affiliation: Department of Cytobiochemistry, University of Łódz, Pomorska 141/143, 90-236 Łódz, Poland.
authors.forename: Jolanta D
authors.initials: JD
authors.lastname: Żołnierczyk
authors.forename: Oxana
authors.initials: O
authors.lastname: Komina
authors.forename: Jerzy Z
authors.initials: JZ
authors.lastname: Błoński
authors.forename: Arleta
authors.initials: A
authors.lastname: Borowiak
authors.forename: Barbara
authors.initials: B
authors.lastname: Cebula-Obrzut
authors.forename: Piotr
authors.initials: P
authors.lastname: Smolewski
authors.forename: Paweł
authors.initials: P
authors.lastname: Robak
authors.forename: Zofia M
authors.initials: ZM
authors.lastname: Kiliańska
authors.forename: Józefa
authors.initials: J
authors.lastname: Węsierska-Gądek
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D017338:Cladribine / Q000494:pharmacology; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D008875:Middle Aged; D011687:Purines / Q000494:pharmacology*; D000077546:Roscovitine; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D011687:Purines; D000077546:Roscovitine; D017338:Cladribine; C048341:mafosfamide; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine
references.citation: J Immunol Methods. 1991 Jun 3;139(2):271-9
references.pmid: 1710634
references.citation: Biochem J. 2001 Nov 1;359(Pt 3):537-46
references.pmid: 11672427
references.citation: J Cell Biochem. 2008 Dec 1;105(5):1161-71
references.pmid: 18846503
references.citation: Blood. 2010 May 13;115(19):3916-22
references.pmid: 20071661
references.citation: Oncol Rep. 2006 Dec;16(6):1389-95
references.pmid: 17089066
references.citation: Mol Cancer Ther. 2005 Jan;4(1):113-24
references.pmid: 15657359
references.citation: J Cell Biochem. 2000 Sep 18;80(1):85-103
references.pmid: 11029756
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):13944-9
references.pmid: 16166262
references.citation: Leuk Res. 2009 Feb;33(2):308-14
references.pmid: 18676014
references.citation: N Engl J Med. 2005 Feb 24;352(8):804-15
references.pmid: 15728813
references.citation: Nature. 1970 Aug 15;227(5259):680-5
references.pmid: 5432063
references.citation: Expert Opin Investig Drugs. 2006 Jan;15(1):23-38
references.pmid: 16370931
references.citation: Ann Oncol. 1998 Jul;9(7):717-20
references.pmid: 9739436
references.citation: Curr Pharm Des. 2011;17(3):256-71
references.pmid: 21348827
references.citation: Blood. 2010 Nov 25;116(22):4430-5
references.pmid: 20713960
references.citation: Cytometry A. 2007 Mar;71(3):125-31
references.pmid: 17252584
references.citation: J Cell Biochem. 2010 Jan 1;109(1):217-35
references.pmid: 19911397
references.citation: Nature. 2004 Dec 2;432(7017):635-9
references.pmid: 15577913
references.citation: N Engl J Med. 2000 Dec 28;343(26):1910-6
references.pmid: 11136261
references.citation: J Cell Biochem. 2007 Mar 1;100(4):865-74
references.pmid: 17203463
references.citation: Nat Rev Clin Oncol. 2009 Jul;6(7):405-18
references.pmid: 19488076
references.citation: Am J Hematol. 2004 Jan;75(1):22-33
references.pmid: 14695629
references.citation: Br J Cancer. 2007 Jan 15;96(1):29-37
references.pmid: 17179992
references.citation: Blood. 2008 Apr 1;111(7):3322-30
references.pmid: 18362212
references.citation: Blood. 1975 Aug;46(2):219-34
references.pmid: 1139039
references.citation: Leuk Lymphoma. 2009 May;50(5):773-80
references.pmid: 19367498
references.citation: Hematol Oncol. 2000 Sep;18(3):87-98
references.pmid: 11027978
references.citation: Expert Rev Anticancer Ther. 2010 Sep;10(9):1389-94
references.pmid: 20836674
references.citation: Cancer Res. 2001 Sep 15;61(18):6640-8
references.pmid: 11559527
references.citation: J Cell Biochem. 2009 Apr 1;106(5):937-55
references.pmid: 19180585
references.citation: Drugs. 2009;69(17):2415-49
references.pmid: 19911856
references.citation: J Hematol Oncol. 2009 Jul 20;2:29
references.pmid: 19619273
references.citation: JAMA. 2011 Jan 5;305(1):59-67
references.pmid: 21205967
references.citation: Blood. 2006 Feb 1;107(3):885-91
references.pmid: 16219797
references.citation: Leuk Lymphoma. 2002 Sep;43(9):1755-62
references.pmid: 12685828
references.citation: Leukemia. 2004 Apr;18(4):747-55
references.pmid: 14973497
references.citation: Blood. 2009 Apr 16;113(16):3652-3
references.pmid: 19372264
references.citation: Blood. 1996 Jun 15;87(12):4990-7
references.pmid: 8652811
references.citation: Cancer Detect Prev. 2004;28(6):433-42
references.pmid: 15582267
references.citation: Biochim Biophys Acta. 1981 Aug 27;655(1):9-17
references.pmid: 7260092
references.citation: PLoS One. 2009 Sep 25;4(9):e7169
references.pmid: 19779621
references.citation: Cell Death Differ. 2003 Apr;10(4):477-84
references.pmid: 12719725
references.citation: Ann N Y Acad Sci. 2009 Aug;1171:124-31
references.pmid: 19723046
references.citation: Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15524-9
references.pmid: 12434020
references.citation: Int J Cancer. 2003 Sep 10;106(4):486-95
references.pmid: 12845642
references.citation: J Clin Oncol. 2007 Mar 1;25(7):793-8
references.pmid: 17283364
references.citation: J Med Chem. 1997 Feb 14;40(4):408-12
references.pmid: 9046330
references.citation: Expert Opin Investig Drugs. 2005 Apr;14(4):457-77
references.pmid: 15882121
references.citation: Best Pract Res Clin Haematol. 2010 Mar;23(1):85-96
references.pmid: 20620973
references.citation: Lancet. 2007 Jul 21;370(9583):230-239
references.pmid: 17658394
references.citation: Cytometry. 1983 Mar;3(5):323-7
references.pmid: 6188586
references.citation: Blood. 2005 Aug 1;106(3):1042-7
references.pmid: 15827128
references.citation: Blood. 1999 Oct 15;94(8):2836-43
references.pmid: 10515887
references.citation: Proc Natl Acad Sci U S A. 1983 Jul;80(13):4045-9
references.pmid: 6191328
references.citation: Blood. 1998 May 1;91(9):3379-89
references.pmid: 9558396
references.citation: Hematol J. 2002;3(5):244-50
references.pmid: 12391542
references.citation: Future Med Chem. 2009 Dec;1(9):1561-81
references.pmid: 21425979
references.citation: Blood. 2006 Jul 15;108(2):473-9
references.pmid: 16551966
references.citation: Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350-4
references.pmid: 388439
references.citation: Blood. 2005 Jun 1;105(11):4484-91
references.pmid: 15692065
references.citation: Rev Clin Exp Hematol. 2000 Mar;4(1):5-21
references.pmid: 11491097
references.citation: Blood. 2009 Apr 16;113(16):3801-8
references.pmid: 18941118
references.citation: Best Pract Res Clin Haematol. 2010 Mar;23(1):155-66
references.pmid: 20620979
references.citation: Nat Rev Cancer. 2002 Aug;2(8):594-604
references.pmid: 12154352
references.citation: Leuk Lymphoma. 2010 Aug;51(8):1371-4
references.pmid: 20687794
references.citation: Science. 1966 Dec 30;154(3757):1662-5
references.pmid: 5924199
references.citation: Int J Cancer. 2002 Dec 10;102(5):463-8
references.pmid: 12432547
references.citation: J Biol Chem. 1951 Nov;193(1):265-75
references.pmid: 14907713
references.citation: Leukemia. 1997 Aug;11(8):1253-7
references.pmid: 9264378
references.citation: J Clin Oncol. 2010 Apr 10;28(11):1863-9
references.pmid: 20212251