Neutropenia is a severe adverse effect that can occur when treating patients with imatinib mesylate for advanced-stage chronic myelogenous leukaemia (CML). Therefore, we evaluated in vitro the combined effect of imatinib and granulocyte colony-stimulating factor (G-CSF) on proliferation and apoptosis of Bcr-Abl-expressing leukaemic cells to infer the safety of G-CSF administration. In KU812 and K562 cell lines, G-CSF neither stimulated their proliferation nor abolished the suppressive effect of imatinib. However, it stimulated the proliferation of blast cells in 2 out of the 5 cases with advanced-stage CML. These in vitro studies appear to provide data for the decision of G-CSF administration in combination with imatinib in the treatment of neutropenic patients with advanced-stage CML.

Keywords:
Apoptosis, Chronic myelogenous leukaemia, Granulocyte colony-stimulating factor, Imatinib mesylate, In vitro proliferation assay, Neutropenia
1.
Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL: Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031–1037.
2.
Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R, Talpaz M: Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001;344:1038–1042.
3.
Talpaz M, Silver RT, Druker BJ, Goldman JM, Gambacorti-Passerini C, Guilhot F, Schiffer CA, Fischer T, Deininger MW, Lennard AL, Hochhaus A, Ottmann OG, Gratwohl A, Baccarani M, Stone R, Tura S, Mahon FX, Fernandes-Reese S, Gathmann I, Capdeville R, Kantarjian H, Sawyers CL: Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 2002;99:1928–1937.
4.
Sawyers CL, Hochhaus A, Feldman E, Goldma JM, Miller CB, Ottmann OG, Schiffer CA, Talpaz M, Guilhot F, Deininger MW, Fischer T, O’Brien SG, Stone RM, Gambacorti-Passerini C, Russell NH, Reiffers JJ, Shea TC, Chapuis B, Coutre S, Tura S, Morra E, Larson RA, Saven A, Peschel C, Gratwohl A, Mandelli F, Ben-Am M, Gathmann I, Capdeville R, Paquette RL, Druker BJ: Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 2002;99:3530-3539.
5.
Kantarjian H, Cortes J, O’Brien S, Giles FJ, Albitar M, Rios MB, Shan J, Faderl S, Garcia-Manero G, Thomas DA, Resta D, Talpaz M: Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Blood 2002;99:3547–3553.
6.
Kantarjian H, Sawyers CL, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, Niederwieser D, Resta C, Capdeville R, Zoellner U, Talpaz M, Druker BJ: Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002;346:645–652.
7.
Sneed TB, Kantarjian H, Talpaz M, O’Brien S, Rios MB, Bekele BN, Zhou X, Resta D, Wierda W, Faderl S, Giles F, Cortes JE: The significance of myelosuppression during therapy with imatinib mesylate in patients with chronic myelogenous leukemia in chronic phase. Cancer 2004;100:116–121.
8.
O’Brien S, Guilhot F, Larson A, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T, Lechner K, Nielsen JL, Rousselot P, Simonsson B, Gratwohl A, Goldman JM, Kantarjian H, Taylor K, Verhoef G, Bolton AE, Capdeville R, Druker BJ: Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348:994–1004.
9.
Kantarjian H, Talpaz M, O’Brien S, Giles F, Garcia-Manero G, Faderl S, Thomas D, Shan J, Rios MB, Cortes JE: Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood 2003;101:473– 475.
10.
Ward AC, Smith L, de Koning JP, van Aesch Y, Touw IP: Multiple signals mediate proliferation, differentiation, and survival from the granulocyte colony-stimulating factor receptor in myeloid 32D cells. J Biol Chem 1999;274:14956–14962.
11.
Crawford J, Ozer H, Stoller R, Johnson D, Lyman G, Tabbara I, Kris M, Grous J, Picozzi V, Rausch G, Smith R, Gradishar W, Yahanda A, Vincent M, Stewart M, Glaspy J: Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med 1991;325:164–170.
12.
Pettengell R, Gurney H, Radford JA, Deakin DP, James R, Wilkinson PM, Kane K, Bentley J, Crowther D: Granulocyte colony-stimulating factor to prevent dose-limiting neutropenia in non-Hodgkin’s lymphoma: a randomized controlled trial. Blood 1992;80:1430–1436.
13.
Heim D, Ebnöther M, Meyer-Monard S, Tsakiris D, Linn M, Tichelli A, Gratwohl A: G-CSF for imatinib-induced neutropenia. Leukemia 2003;17:805–807.
14.
Marin D, Marktel S, Foot N, Bua M, Goldman JM, Apperley JF: Granulocyte colony-stimulating factor reverses cytopenia and may permit cytogenetic responses in patients with chronic myeloid leukemia treated with imatinib mesylate. Haematologica 2003;88:227–229.
15.
Quintas-Cardama A, Kantarjian H, O’Brien S, Garcia-Manero G, Rios MB, Talpaz M, Cortes J: Granulocyte-colony-stimulating factor (filgrastim) may overcome imatinib-induced neutropenia in patients with chronic-phase chronic myelogenous leukemia. Cancer 2004;100:2592–2597.
16.
Meyerson HJ, Farhi DC, Rosenthal NS: Transient increase in blasts mimicking acute leukemia and progressing myelodysplasia in patients receiving growth factor. Am J Clin Pathol 1998;109:675–681.
17.
Morton J, Mollee P, Taylor K, Grigg A, Durrant S, Moore D, Rodwell R, Eliadis P, Hutchins C, Williams B, Seeley G, Wright S, Kelly C, Rentoul A, Iland H, Atkinson K, Januszewicz H, Bunce I, Bashford J, Stewart C, Taylor D: Safe mobilization of normal progenitors in advanced chronic myeloid leukemia with intensive chemotherapy and granulocyte colony-stimulating factor. Leuk Res 1999;23:177–183.
18.
American Society of Clinical Oncology: Recommendations for the use of hematopoietic colony-stimulating factors: evidence-based clinical practice guidelines. J Clin Oncol 1994;12:2471–2508.
19.
Kishi K: A new leukemia cell line with Philadelphia chromosome characterized as basophil precursors. Leuk Res 1985;9:381–390.
20.
Lozzio CB, Lozzio BB: Human chronic myelogenous leukemia cell line with positive Philadelphia chromosome. Blood 1975;45:321–334.
21.
Alvarez S, MacGrogan D, Rodriguez-Perales S, Martinez-Ramirez A, Urioste M, Benitez J, Nimer SD, Cigudosa JC: Cytogenetic characterization reveals that the SAM-1 erythroid cell line is derived from K-562 cells. Blood 2002;100:3435.
22.
Ogata K, Nakamura K, Yokose N, Tamura H, Tachibana M, Taniguchi O, Iwakiri R, Hayashi T, Sakamaki H, Murai Y, Tohyama K, Tomoyasu S, Nonaka Y, Mori M, Dan K, Yoshida Y: Clinical significance of phenotypic features of blasts in patients with myelodysplastic syndrome. Blood 2002;100:3887–3896.
23.
van Engeland M, Ramaekers FC, Schutte B, Reutelingsperger CP: A novel assay to measure loss of plasma membrane asymmetry during apoptosis of adherent cells in culture. Cytometry 1996;24:131–139.
24.
Tsuzuki M, Ezaki K, Maruyama F, Ino T, Kojima H, Okamoto M, Yamaguchi T, Nomura T, Miyazaki H, Wakita M, Matsui T, Hirano M: Proliferative effects of several hematopoietic growth factors on acute myelogenous leukemia cells and correlation with treatment outcome. Leukemia 1997;11:2125–2130.
25.
Mauro MJ, Kurilik G, Balleisen S, O’Dwyer ME, Reese SF, Druker BJ: Myeloid growth factors for neutropenia during imatinib mesylate (STI571) therapy for CML: preliminary evidence of safety and efficacy. Blood 2001;98:139.
26.
Inukai T, Sugita K, Mitsui K, Iijima K, Goi K, Tezuka T, Kojika S, Kagami K, Mori T, Kinoshita A, Suzuki T, Okazaki-Koyama T, Nakazawa S: Participation of granulocyte colony-stimulating factor in the growth regulation of leukemia cells from Philadelphia chromosome-positive acute leukemia and blast crisis of chronic myeloid leukemia. Leukemia 2000;14:1386–1395.
27.
Layton JE, Hockman H, Sheridan WP, Morstyn G: Evidence for a novel in vivo control mechanism of granulopoiesis: mature cell-related control of a regulatory growth factor. Blood 1989;74:1303–1307.
28.
Jiang X, Lopez A, Holyoake T, Eaves A, Eaves C: Autocrine production and action of IL-3 and granulocyte colony-stimulating factor in chronic myeloid leukemia. Proc Natl Acad Sci USA 1999;96:12804–12809.
29.
Ward AC, Hermans MH, Smith L, van Aesch YM, Schelen AM, Antonissen C, Touw IP: Tyrosine-dependent and -independent mechanisms of STAT3 activation by the human granulocyte colony-stimulating factor (G-CSF) receptor are differently utilized depending on G-CSF concentration. Blood 1999;93:113–124.
30.
Hermans MH, van de Geijn GJ, Antonissen C, Gits J, van Leeuwen D, Ward AC, Touw IP: Signaling mechanisms coupled to tyrosines in the granulocyte colony-stimulating factor receptor orchestrate G-CSF-induced expansion of myeloid progenitor cells. Blood 2003;101:2584–2590.
31.
Suzuki K, Hino M, Hato F, Tatsumi N, Kitagawa S: Cytokine-specific activation of distinct mitogen-activated protein kinase subtype cascades in human neutrophils stimulated by granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor-alpha. Blood 1999; 93:341–349.
32.
Hunter MG, Avalos BR: Phosphatidylinositol 3′-kinase and SH2-containing inositol phosphatase (SHIP) are recruited by distinct positive and negative growth-regulatory domains in the granulocyte colony-stimulating factor receptor. J Immunol 1998;160:4979–4987.
33.
Uddin S, Hussain AR, Al-Hussein KA, Manogaran PS, Wickrema A, Gutierrez MI, Bhatia KG: Inhibition of phosphatidylinositol 3′-kinase/AKT signaling promotes apoptosis of primary effusion lymphoma cells. Clin Cancer Res 2005;11:3102–3108.
34.
Maianski NA, Mul FP, van Buul JD, Roos D, Kuijpers TW: Granulocyte colony-stimulating factor inhibits the mitochondria-dependent activation of caspase-3 in neutrophils. Blood 2002;99:672–679.
35.
Asano Y, Shibuya T, Okamura S, Morioka E, Taniguchi S, Niho Y: Synergism of leukemic blast growth factors in medium conditioned by human bladder carcinoma cell line 5637. Int J Cell Cloning 1987;5:504–510.
36.
Nara N, Murohashi I, Suzuki T, Yamashita Y, Maruyama Y, Aoki N, Tanikawa S, Onozawa Y: Effects of recombinant human granulocyte colony-stimulating factor (G-CSF) on blast progenitors from acute myeloblastic leukaemia patients. Br J Cancer 1987;56:49–51.
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2006
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