A novel approach to treatment in childhood acute myeloblastic leukemia and myelodysplastic syndrome with high-dose methylprednisolone as a differentiation- and apoptosis-inducing agent of myeloid leukemic cells

HİÇSÖNMEZ, Gönül

A novel approach to treatment in childhood acute myeloblastic leukemia and myelodysplastic syndrome with high-dose methylprednisolone as a differentiation- and apoptosis-inducing agent of myeloid leukemic cells

Gönül HİÇSÖNMEZ (Hacettepe Üniversitesi, Tıp Fakültesi, İhsan Doğramacı Çocuk Hastanesi, Ankara, Türkiye)

Turkish Journal of Hematology

1 0

Yıl: 2010 Cilt: 27 Sayı: 1 Sayfa Aralığı: 1 - 7 Metin Dili: Türkçe İndeks Tarihi: 29-07-2022

A novel approach to treatment in childhood acute myeloblastic leukemia and myelodysplastic syndrome with high-dose methylprednisolone as a differentiation- and apoptosis-inducing agent of myeloid leukemic cells

Öz:

Akut Promyelositik Lösemili (APL) çocuklarda, lösemik hücrenin normal hücreye dönüşünü (farklIlaşma) sağlayan all-transretinioik asidin (ATRA) kullanılmasI ile tedavi sonuçlarInda önemli ilerlemeler elde edilmiştir. Bu nedenle APL dIşInda diğerakut myeloblastik lösemi (AML) subtiplerinde lösemik hücrelerin farklIlaşmasInI sağlayan ilaçlarIn kullanIlmsI, bu hastalar içinde önemli ve ümit verici bir tedavi yaklaşImI olacaktIr. Fare myeloid lösemik hücrelerin steroid ile farklIlaşmasInInsağlanabileceğini gösteren in vitro çalIşmalara dayanarak, biz de, literatürde ilk defa olmak üzere, AML’li çocuklarIn farklIsubtiplerinde (AML M1,-M2,-M3,-M4,-M7), kIsa süreli yüksek doz metilprednizolon (YDMP) tedavisi ile lösemik hücrelerinnormal hücrelere dönebileceğini gösterdik. Ayrıca YDMP tedavisi, lösemik hücreden dönüşen veya direkt olarak myeloidlösemik hücrelerin apoptotik ölümüne neden olmaktadIr. Diğer lösemi ilaçlarI kullanIlmaksIzIn YDMP, hastalara verildikten kIsa süre sonra , kilinik bulgularda düzelme, periferik kanve kemik iliği lösemi hücrelerinde önemli bir azalma ve kemik iliği dIşIndaki lösemi hücre kitlesinin hIzla küçülmesine neden olmaktadIr. YDMP’ nun sitotoksik tedavi protokollarIna ilavesi ile hastalarIn remisyon yüzdeleri artmIş ve hastalIksIz yaşamsüreleri uzamIştIr. Bu nedenlerle, YDMP ile yapIlacak kilinik çalIşmalarIn, AML ve myelodisplastik sendromlu çocuklarIntedavilerinden alInacak sonuçlara önemli katkIsI olacağI kanIsIndayIz.

Anahtar Kelime:

Konular: Hematoloji

Çocukluk yaşı akut myeloblastik lösemi ve myelodisplastik sendromunda myeloid lösemik hücrelerde farklılaşma ve apoptosisi sağlayan yüksek doz metilprednizolon ile yeni bir tedavi yaklaşımı

Öz:

Differentiation-inducing therapy with all-trans retinoic acid significantly improved the outcome in children with acutepromyelocytic leukemia (APL). Therefore, use of agents that induce differentiation of leukemic cells in non-APL childrenappears to be a highly promising therapeutic approach. Based on the experimental studies in mice, we have shown thatshort-course high-dose methylprednisolone (HDMP) treatment can induce terminal differentiation of leukemic cells inchildren with various subtypes of acute myeloblastic leukemia (AML-M1,-M2,-M3,-M4,-M7). It has also been shown toinduce apoptosis of myeloid leukemic cells with or without differentiation. Administration of HDMP as a single agentresulted in a rapid clinical improvement, a marked decrease in blast cells in both peripheral blood and bone marrow anddramatic decreases in the size of extramedullary leukemic mass in children with AML and myelodysplastic syndrome(MDS). Addition of HDMP to cytotoxic chemotherapy regimens increased the remission rate and improved the outcomein these children. Future clinical trials with HDMP would contribute to further improvements in the treatment results in thesechildren.

Anahtar Kelime:

Konular: Hematoloji

Belge Türü: Makale Makale Türü: Derleme Erişim Türü: Erişime Açık

1. Ranney HM, Gelhorn A. The effect of massive prednisone and prednisolone therapy in leukemia and lymphoma. Am J Med 1957;22:405-13.
2. Shanbrom E, Miller S. Critical evaluation of massive steroid therapy of acute leukemia. N Engl J Med 1962;266:1354-8.
3. Granville NB, Rubio F, Unugur A, Schulman E, Dameshek W. Treatment of acute leukemia in adults with massive doses of prednisone and prednisolone. N Engl J Med 1958;259:207-13.
4. Haarman EG, Kaspers GJL, Pieters R, Rottier MMA, Veerman AJP. Circumvention of glucocorticoid resistance in childhood leukemia. Leuk Res 2008;32:1417-23.
5. Uckan D, Yetgin S, Cetin M, Özyürek E, Okur H, Aslan D, Tuncer M. The effects of high-dose methylprednisolone on apoptosis in children with acute lymphoblastic leukemia. Clin Lab Haematol 2003;25:35-40.
6. Erduran E, Tekelioglu Y, Karakas T, Gedik Y, Mert FM. Comparison of the apoptotic effects on lymphoblasts and on increase of myeloid lineage cells of a short-time high-dose methylprednisolone and the conventional-dose prednisolone treatments in children with acute lymphoblastic leukemia. Pediatr Hematol Oncol 2006;23:587-98.
7. Schwartz E, Thompson EB, Gelber RD, Young RD, Chilton D, Cohen HJ, Sallan SE. Improved response with higher corticosteroid dose in children with acute lymphoblastic leukemia. J Clin Oncol 2001;19:1040-6.
8. Ryalls MR, Pinkerton CR, Meller ST, Talbot D, McElwain TJ. High-dose methylprednisolone sodium succinate as a single agent in relapsed childhood acute lymphoblastic leukemia. Med Pediatr Oncol 1992;20:119-23.
9. Hicsonmez G, Ozsoylu S, Onat N, Prozorva VZ, Gümrük F, Tuncer M. High-dose methylprednisolone in resistant and relapsed children with acute lymphoblastic leukemia. Med Pediatr Oncol 1994;22:68-9.
10. Hicsonmez G, Gümrük F, Zamani VP, Tuncer MA, Yetgin S, Gürgey A, Atahan L, Özsoylu S. High-dose methylprednisolone for children with acute lymphoblastic leukemia and unfavorable presenting features. Eur J Haematol 1997;58:26-31.
11. Yetgin S, Cetin M. The dose related effect of steroids on blast reduction rate and event free survival in children with acute lymphoblastic leukemia. Leuk Lymphoma 2003;44:489-95.
12. Yetgin S, Tuncer MA, Cetin M, Gümrük F, Yenicesu, I, Tunc B, Öner AF, Toksoy H, Koç A, Aslan D, Özyürek E, Olcay L, Atahan L, Tunçbilek E, Gürgey Ae. Benefit of high-dose methyl-prednisolone in comparison with conventional-dose prednisolone during remission induction therapy in childhood acute lymphoblastic leukemia for long-term follow-up. Leukemia 2003;17:328-33.
13. Rubnitz JE, Gibson B, Smith FO. Acute myeloid leukemia. Pediatr Clin N Am 2008;55:21-51.
14. Woods WG. Curing childhood acute myeloid leukemia (AML) at the half-way point: promises to keep and miles to go before we sleep. Pediatr Blood Cancer 2006;46:565-9.
15. Testi AM, Biondi A, Lo Coco F, Moleti ML, Giona F, Vignetti M, Menna G, Locatelli F, Pession A, Barisone E, De Rossi G, Diverio D, Micalizzi C, Aricò M, Basso G, Foa R, Mandelli F. GIMEMA-AIEOP AIDA protocol for the treatment of newly diagnosed acute promyelocytic leukemia (APL) in children. Blood 2005;106:447-53.
16. Mantadakis E, Samonis G, Kalmanti M. A comprehensive review of acute promyelocytic leukemia in children. Acta Haematol 2008;119:73-82.
17. Chen Z, Chen GQ, Shen ZX, Chen SJ, Wang ZY. Treatment of acute promyelocytic leukemia with arsenic compounds: in vitro and in vivo studies. Semin Hematol 2001;38:26-36.
18. Zhang L, Zhao H, Zhu X, Chen Y, Zou Y, Chen X. Retrospective analysis of 65 Chinese children with acute promyelocytic leukemia: a single center experience. Pediatr Blood Cancer 2008;51:210-5.
19. Lotem J, Sachs L. Induction of specific changes in the surface membrane of myeloid leukemic cells by steroid hormones. Int J Cancer 1975;15:731-40.
20. Krystosek A, Sachs L. Steroid hormone receptors and the differentiation of myeloid leukemic cells. J Cell Physiol 1977;92:345-52.
21. Sachs L. Control of normal cell differentiation and the phenotypic reversion of malignancy in myeloid leukemia. Nature 1978;274:535-9.
22. Honma Y, Kasukabe T, Okabe J, Hozumi M. Glucocorticoid induced differentiation of cultured mouse myeloid leukemic cells. Gunn 1977;68:241-6.
23. Kasukabe T, Honma Y, Hozumi M, Suda T, Nishii Y. Control of proliferating potential of myeloid leukemia cells during long-term treatment with vitamin D3 analogues and other differentiation inducers in combination with antileukemic drugs. In vitro and in vivo studies. Cancer Res 1987;47:567-72.
24. Nakamaki T, Sakashita A, Sano M, Hino K, Suziki K, Tomayasu S, Tsuruoka N. Differentiation induction of myeloid leukemia cells by glucocorticoid - the differentiation induction effect in vitro and in vivo. Rinsho Ketsueki 1989;30:149-57.
25. Ovali E, Özdemir F, AydÕn F, KavgacÕ H, Tekelioglu Y, Büyükcelik A, YÕlmaz M. The effects of dexamethasone on leukemic cells derived from patients with AML. J Exp Clin Cancer Res 2003;22:85-9.
26. Özbek N, Erdemli E, Hicsonmez G, Okur H, Tekelioglu M. Effect of methylprednisolone on human myeloid leukemic cells in vitro. Am J Hematol 1999;60:255-9.
27. Song LN, Cheng T. Glucocorticoid-induced growth inhibition and differentiation of a human megakaryoblastic leukemia cell line. Involvement of glucocorticoid receptor. Stem Cells 1993;11:312-8.
28. Miyoshi H, Ohki M, Nakagawa T, Honma Y. Glucocorticoids induce apoptosis in acute myeloid leukemia cell lines with a t (8;21) chromosome translocation. Leuk Res 1997;21:45-50.
29. Uzunoglu S, Uslu R, Töbü M, Saydam G Terzioglu E Büyükkeçeci F. Augmentation of methylprednisolone-induced differentiation of myeloid leukemia cells by serine/threonine phosphatase inhibitors. Leuk Res 1999;23:507-12.
30. Omay SB, Saydam G, AydÕn HH, Selvi N, Öktem G, SanlÕ UA, Tobu M, Büyükkeçeci F. Potential involvement of calcineurin regulating the state of differentiation and apoptosis of HL-60 cells during methylprednisolone treatment. Turk J Hematol 2003;20:143-51.
31. Özcimen A, Cetin M. Methylprednisolone induces terminal differentiation in the U-937 human myelomonocytic leukemia cells. Turk J Immunol 2008;13:10-4.
32. Corsello SM, Roti G, Ross KN, Chow KT, Galinsky D, DeAngelo DJ, Stone RM, Kung AL, Golup TR, Stegmaier K. Identification of AML1-ETO modulators by chemical genomics. Blood 2009;113:6193-205.
33. Hicsonmez G, Ozsoylu S, Tuncer AM. Differentiation of myeloid leukemic cells induced by high-dose methylprednisolone in patients with acute myeloblastic leukemia and its therapeutic potential. Leuk Res 1991;15:537-41.
34. Hicsonmez G. The effect of steroid on myeloid leukemic cells: the potential of short-course high-dose methylprednisolone treatment in inducing differentiation, apoptosis and in stimulating myelopoiesis. Leuk Res 2006;30:60-8.
35. Chow JM, Liu CR, Lin CP, Lee CN, Cheng YC, Lin S, Liu HE. Downregulation of c-Myc determines sensitivity to 2-methoxyestradiol-induced apoptosis in human acute myeloid leukemia. Exp Hematol 2008;36:140-8.
36. Trafalis DTP, Sambani C, Kapsimali V, Economidou J, Politis G, Catsoulacos P. Effects of homo-aza-steroids on acute nonlymphoblastic leukemia cell proliferation in vitro. Br J Haematol 1995;91:907-14.
37. He Q, Jiang D. A novel aminosteroid is active for proliferation inhibition and differentiation induction of human acute myeloid leukemia HL-60 cells. Leuk Res 1999;23:369-72.
38. Thibeault D, Roy J, DeRoy P, Poirier D. Chemical synthesis of 2`-amino-5_-androstane-3_, 17` -diol N-derivatives and their antiproliferative effect on HL- 60 human leukemia cells. Bioorg Med Chem 2008;16:5062-77.
39. Zhang L, Nakaya K, Yoshida T. Induction by bufalin of differentiation of human leukemia cells HL60, U937, and ML1 toward macrophage/monocyte-like cells and its potential synergistic effect on the differentiation of human leukemia cells in combination with other inducers. Cancer Res 1992;52:4634-41
40. Yamada K, Hino K-I, Tomoyasu S, Honma Y, Tsuruoka N. Enhancement by bufalin of retinoic acid-induced differentiation of acute promyelocytic leukemia cells in primary culture. Leuk Res 1998;22:589-95.
41. Zhou JY, Norman AW, Akashi M, Akashi M, Chen DL, Uskokovic MR, Aurrecoechea JM, Koeffler HP. Development of a novel 1,25 (OH)2-vitamin D3 analog with potent ability to induce HL-60 cell differentiation without modulating calcium metabolism. Blood 1991;78:75-82.
42. Samudio I, Konopleva M, Safe S, McQueen T, Andreeff M. Guggulsterones induce apoptosis and differentiation in acute myeloid leukemia: identification of isomer-specific antileukemic activities of the pregnadienedione structure. Mol Cancer Ther 2005;4:1982-92.
43. Hicsonmez G, Ozsoylu S, Tuncer M, Erer B. High-dose intravenous methylprednisolone in the treatment of acute nonlymphoblastic leukemia with ocular involvement. Turk J Pediatr 1988;30:181-3.
44. Hicsonmez G, Ozsoylu S, Gurgey A, Zamani VP, Irken G. High dose methylprednisolone for remission induction in children with acute nonlymphoblastic leukemia. Eur J Haematol 1989;42:498-500.
45. Hicsonmez G, Ozsoylu S, Tuncer A, Ertürk G, Ozbek N, Karadeniz N. Direct morphological evidence of high-dose methylprednisolone-induced maturation of leukemic cells in children with acute nonlymphoblastic leukemia. Exp Hematol 1991;19:232-3.
46. Hicsonmez G, Tuncer AM, Guler E, Tan E, Tekelioglu M. The potential role of high-dose methylprednisolone on the maturation of leukemic cells in children with acute promyelocytic leukemia (APL). Exp Hematol 1993;21:599-601.
47. Hicsonmez G, Tuncer AM, Toksoy HB, Yenicesu I, Cetin M. Differentiation of myeloid leukemic cells induced by short-course high-dose methylprednisolone in patients with different subtypes of acute myeloblastic leukemia. Leuk Lymphoma 1999;33:573-80.
48. Hicsonmez G, Cetin M, Aslan D, Ozyurek E. The role of short course of high-dose methylprednisolone in children with acute myeloblastic leukemia (FAB M2) presented with myeloid tumor. Pediatr Hematol Oncol 2003;20:373-9.
49. Hicsonmez G, Cetin M, Okur H, Erdemli E, Gürgey A. The potential effect of short-course high-dose steroid on the maturation and apoptosis of leukemic cells in a child with acute megakaryoblastic leukemia. Leuk Lymphoma 2003; 44:1037-42.
50. Martin SJ, Bradley JG, Cotter TG. HL-60 cells induced to differentiate towards neutrophils subsequently die via apoptosis. Clin Exp Immunol 1990;79:448-53.
51. Hicsonmez G, Erdemli E, Tekelioglu M, Tuncer AM, Ozbek N, Cetin M, Cotter TG. Morphologic evidence of apoptosis in childhood acute myeloblastic leukemia treated by high-dose methylprednisolone. Leuk Lymphoma 1996;22:91-6.
52. Blewitt RW, Abbott AC, Bird CC. Mode of cell death induced in human lymphoid cells by high and low doses of glucocorticoid. Br J Cancer 1983;47:477-86.
53. Bird CC, Robertson AMG, Read J, Currie AR. Cytolethal effects of glucocorticoids in human lymphoblastoid cell lines. J Pathol 1977;123:145-56.
54. Cailleteau C, Liagre B, Battu S, Jayat Vignoles C, Beneytout JL. Increased cyclooxygenase-2 and thromboxane synthase expression is implicated in diosgenin-induced megakaryocytic differentiation in human erythroleukemia cells. Anal Biochem 2008;380:26-34.
55. Lotem J, Sachs L. Regulation of bcl-2, bcl-XL and bax in the control of apoptosis by hematopoietic cytokines and dexamethasone. Cell Growth Differ 1995;6:647-53.
56. Lotem J, Sachs L. Control of sensitivity to induction of apoptosis in myeloid leukemic cells by differentiation and bcl-2 dependent and independent pathways. Cell Growth Differ 1994;5:321-7.
57. Kasukabe T, Okabe-Kado J, Hozumi M, Honma Y. Inhibition by interleukin 4 of leukemia inhibitory factor-, interleukin 6-, and dexamethasone-induced differentiation of mouse myeloid leukemia cells: role of c-myc and junB proto-oncogenes. Cancer Res 1994;54:592-7.
58. Hicsonmez G, Cetin M, Tuncer AM, Yenicesu I, Aslan D, Ozyürek E, Unlü S. Children with acute myeloblastic leukemia presenting with extramedullary infiltration: the effects of high dose steroid treatment. Leuk Res 2004;28:25-34.
59. Hicsonmez G, Karadeniz N, Prozorova ZV, Tuncer AM, Gümrük F, Ertürk G, Gürgey A, Ozsoylu S. High remission rate in acute myeloblastic leukemia in children treated with high-dose methylprednisolone. Eur J Haematol 1992;48:215-20.
60. Sugawara T, Sato A, Shishido T, Okuda M, Kameoka J, Meguro K, Endo K, Yoshinaga K. Complete remission in acute myeloid leukemia after treatment with recombinant human granulocyte colony stimulating factor and high-dose intravenous methylprednisolone. Br J Haematol 1991;77:561-2.
61. Hicsonmez G, Kale G, Erdem G, Bilgic S, Hazar V. Dramatic effect of high-dose methylprednisolone on orbital granulocytic sarcoma. Pediatr Hematol Oncol 1996;13:187-90.
62. Ozyurek E, Alioglu B, Coskun M, Ozbek N. Successful use of short-course high-dose methylprednisolone in a child with acute myeloblastic leukemia (FAB M2) and myeloid tumor. Leuk Lymphoma 2006;28:97-104.
63. Takeda M, Yamaguchi S, Eguchi K, KajÕume T, Nishimura S, Kobayashi M, Kurisu K. Spinal epidural granulocytic sarcoma in a child precedent to clinical manifestation of acute myeloid lymphoma. Neurol Med Chir. 2009;49:221-4.
64. Hicsonmez G, Cetin M, Tunc B, Tuncer AM, Gümrük F, Yenicesu I. Dramatic resolution of pleural effusion in children with chronic myelomonocytic leukemia following short-course high-dose methylprednisolone. Leuk Lymphoma 1998;29:617-23.
65. Hicsonmez G, Gurgey A, Zamani VP, Yetgin S, Altay C, Ozsoylu S. Poor prognosis in children with acute nonlymphoblastic leukemia in Turkey. Am J Pediatr Hematol/Oncol 1988;10:268-73.
66. Hicsonmez G, Tuncer AM, SaylÕ T, Güler E, Cetin M, Mufti GJ. High-dose methylprednisolone, low-dose cytosine arabinoside and mitoxantrone in children with myelodysplastic syndromes. Hematol Pathol 1995;9:185-93.
67. Tunc B, Oner AF, Hicsonmez G. The effect of high-dose methylprednisolone on peripheral blood lymphocyte subsets in children with acute leukemia during remission induction treatment. Leuk Res 2003;27:19-21.
68. Vitale C, Cottalasso F, Montaldo E, Moretta L, Mingari MC. Methylprednisolone induces preferential and rapid differentiation of CD34+cord blood precursors toward NK cells. Int Immunol 2008;20:565-75.
69. Suzuki K, Ohishi K, Sekine T, Masoya M, Katayama N. Selective blast cell reduction in elderly patients with acute myeloid leukemia secondary to myelodysplastic syndrome treated with methylprednisolone. Int J Hematol 2007;85:344-9.
70. Shimohakamada Y, Shinohara K, Fukuda N. Remission of acute myeloblastic leukemia after severe pneumonia treated with high-dose methylprednisolone. Int J Hematol 2001;74:173-7.
71. Tuncer AM, Hicsonmez G, Gumruk F, Albayrak D, Duru F, Güzel E, SaylÕ T. The effect of high-dose methylprednisolone combined chemotherapy on CD34-positive cells in acute lymphoblastic leukemia. Hematol Pathol 1994;8:169-75.
72. Cetin M, Hicsonmez G, Tuncer AM, Kansu E, CanpÕnar H. The effect of short-course high-dose corticosteroid therapy on peripheral blood CD34+progenitor cells in children with acute leukemia. Exp Hematol 1996;24:1191-4.
73. Tunc B, Oner AF, Hicsonmez G. The effect of short-course high-dose methylprednisolone on peripheral blood CD34+ progenitor cells of children with acute leukemia during remission induction therapy. Turk J Pediatr 2002;44:1-4.
74. Elmas SA, Cetin M, Tuncer M, Hicsonmez G. Myeloprotective effect of short-course high-dose methylprednisolone treatment before consolidation therapy in children with acute myeloblastic leukemia. Am J Hematol 2005;80:1-5.
75. Niemeyer CM, Baumann I. Myelodysplastic syndrome in children and adolescents. Semin Hematol 2008;45:60-70.
76. Creutzig U, Bender- Götze C, Ritter C, Zimmermann M, Stollmann-Gibbels B, Körholz D, Niemeyer C. The role of intensive AML-specific therapy in treatment of children with RAEB and RAEB-t. Leukemia 1998;12:652-9.
77. Morosetti R, Koeffler HP. Differentiation therapy in MDS. Semin Hematol 1996;33:236-45.
78. Tuncer AM, Pagliuca A, Hicsonmez G, Yetgin G, Ozsoylu S, Mufti GJ. Primary myelodysplastic syndrome in children: the clinical experience in 33 cases. Br J Haematol 1992;82:347-53.
79. Hicsonmez G, Cetin M, Yenicesu I , Olcay L, Koc A, Aktas D, Tuncbilek E, Tuncer AM. Evaluation of children with myelodysplastic syndrome: importance of extramedullary disease as a presenting symptom. Leuk Lymphoma 2001;42:665-74.
80. Yenicesu I, Hicsonmez G, Tuncer AM. Effect of short-course high-dose methylprednisolone treatment on serum IL-2 levels in children with myelodysplastic syndromes. Leuk Res 1997;21:789-91.
81. Yamada T, Tsurumi H, Kasahara S, Hara T, Sawada M, Moriwaki H. Immunosuppressive therapy for myelodysplastic syndrome: efficacy of methylprednisolone pulse therapy with or without cyclosporine A. J Cancer Res Clin Oncol 2003;129:485-91.
82. Motoji T, Teramura M, Takahashi M, Oshimi K, Okada M, Kasukabe K, Mizoguchi M. Successful treatment of refractory anemia with high-dose methylprednisolone. Am J Hematol 1990;33:8-12.
83. Motomura S, Motoji T, Okutomi K, Nishikawa T, Kasajima T, Mizoguchi H. Successful treatment of refractory anemia by high dose methylprednisolone associated with an increment in CD68- positive cells in bone marrow. Am J Hematol 2001;66:80-4.
84. Tuncer AM, Hiçsönmez G, Gümrük F, SaylÕ T, Güler E, Çetin M, Okur H. Serum TNF-alpha, gamma-INF, G-CSF and GM-CSF levels in neutropenic children with acute leukemia treated with short-course high-dose methylprednisolone. Leuk Res 1996;20:265-9.
85. Olofsson T, Sallerfors B. Modulation of the production of leukemia associated inhibitor (LAI) and its interaction with granulocyte-macrophage colony-forming cells. Exp Hematol 1987;15:1163-7.
86. Ohmori S, Ohmori M, Yamagishi M, Okuma M. MDS macrophage derived inhibitory activity on myelopoiesis of MDS abnormal clones. Br J Haematol 1993;83:388-91.
87. Hicsonmez G, Tunc B, Olcay L, Tuncer AM. Effect of short course high-dose steroid therapy in a child with myelodysplastic syndrome. Pediatr Hematol Oncol 2001;18:525-9.
88. Hiçsönmez G, Çetin M, Tuncer AM, Gümrük F, Özbek N, Kara A, Gürgey A. High-dose methylprednisolone for remission induction in hypoplastic acute myeloid leukemia. Eur J Haematol 1995;54:125-6.
89. Bagby GC, Gabourel JD, Linman JW. Glucocorticoid therapy in the preleukemic syndrome (hematopoietic dysplasia): identification of responsive patients using in vitro techniques. Ann Int Med 1980; 92:55-8.
90. Hino K, Nakamaki T. Differentiation therapy for myelodysplastic syndrome. Rinsho Ketsueki 1993;34:283-8.
91. Gumruk F, Tuncer AM, Hiçsönmez G. Pyoderma gangrenosum in a child with myelodysplastic syndrome. Pediatr Hematol Oncol 2000;22:362-4.
92. Pyrstowsky JH, Johnson BU, Bolwell BJ, Lazarus GS. Treatment of cutaneous granulocytic sarcoma in a patient with myelodysplasia. Am J Med 1989;86:477-80.
93. Imai Y, Fukuoka T, Nakatani A, Ohsaka A, Takahashi A. Sustained trilineage recovery and disappearance of abnormal chromosome clone in a patient with myelodysplastic syndrome following combination therapy with cytokines (granulocyte colony-stimulating factor and erythropoietin) and high-dose methylprednisolone. Br J Haematol 1996;93:146-50.
94. George SW, Newman ED. Seronegative inflammatory arthritis in the myelodysplastic syndromes. Semin Arth Rheum 1992;21:345-54.

APA	HİÇSÖNMEZ G (2010). A novel approach to treatment in childhood acute myeloblastic leukemia and myelodysplastic syndrome with high-dose methylprednisolone as a differentiation- and apoptosis-inducing agent of myeloid leukemic cells. , 1 - 7.
Chicago	HİÇSÖNMEZ Gönül A novel approach to treatment in childhood acute myeloblastic leukemia and myelodysplastic syndrome with high-dose methylprednisolone as a differentiation- and apoptosis-inducing agent of myeloid leukemic cells. (2010): 1 - 7.
MLA	HİÇSÖNMEZ Gönül A novel approach to treatment in childhood acute myeloblastic leukemia and myelodysplastic syndrome with high-dose methylprednisolone as a differentiation- and apoptosis-inducing agent of myeloid leukemic cells. , 2010, ss.1 - 7.
AMA	HİÇSÖNMEZ G A novel approach to treatment in childhood acute myeloblastic leukemia and myelodysplastic syndrome with high-dose methylprednisolone as a differentiation- and apoptosis-inducing agent of myeloid leukemic cells. . 2010; 1 - 7.
Vancouver	HİÇSÖNMEZ G A novel approach to treatment in childhood acute myeloblastic leukemia and myelodysplastic syndrome with high-dose methylprednisolone as a differentiation- and apoptosis-inducing agent of myeloid leukemic cells. . 2010; 1 - 7.
IEEE	HİÇSÖNMEZ G "A novel approach to treatment in childhood acute myeloblastic leukemia and myelodysplastic syndrome with high-dose methylprednisolone as a differentiation- and apoptosis-inducing agent of myeloid leukemic cells." , ss.1 - 7, 2010.
ISNAD	HİÇSÖNMEZ, Gönül. "A novel approach to treatment in childhood acute myeloblastic leukemia and myelodysplastic syndrome with high-dose methylprednisolone as a differentiation- and apoptosis-inducing agent of myeloid leukemic cells". (2010), 1-7.

APA	HİÇSÖNMEZ G (2010). A novel approach to treatment in childhood acute myeloblastic leukemia and myelodysplastic syndrome with high-dose methylprednisolone as a differentiation- and apoptosis-inducing agent of myeloid leukemic cells. Turkish Journal of Hematology, 27(1), 1 - 7.
Chicago	HİÇSÖNMEZ Gönül A novel approach to treatment in childhood acute myeloblastic leukemia and myelodysplastic syndrome with high-dose methylprednisolone as a differentiation- and apoptosis-inducing agent of myeloid leukemic cells. Turkish Journal of Hematology 27, no.1 (2010): 1 - 7.
MLA	HİÇSÖNMEZ Gönül A novel approach to treatment in childhood acute myeloblastic leukemia and myelodysplastic syndrome with high-dose methylprednisolone as a differentiation- and apoptosis-inducing agent of myeloid leukemic cells. Turkish Journal of Hematology, vol.27, no.1, 2010, ss.1 - 7.
AMA	HİÇSÖNMEZ G A novel approach to treatment in childhood acute myeloblastic leukemia and myelodysplastic syndrome with high-dose methylprednisolone as a differentiation- and apoptosis-inducing agent of myeloid leukemic cells. Turkish Journal of Hematology. 2010; 27(1): 1 - 7.
Vancouver	HİÇSÖNMEZ G A novel approach to treatment in childhood acute myeloblastic leukemia and myelodysplastic syndrome with high-dose methylprednisolone as a differentiation- and apoptosis-inducing agent of myeloid leukemic cells. Turkish Journal of Hematology. 2010; 27(1): 1 - 7.
IEEE	HİÇSÖNMEZ G "A novel approach to treatment in childhood acute myeloblastic leukemia and myelodysplastic syndrome with high-dose methylprednisolone as a differentiation- and apoptosis-inducing agent of myeloid leukemic cells." Turkish Journal of Hematology, 27, ss.1 - 7, 2010.
ISNAD	HİÇSÖNMEZ, Gönül. "A novel approach to treatment in childhood acute myeloblastic leukemia and myelodysplastic syndrome with high-dose methylprednisolone as a differentiation- and apoptosis-inducing agent of myeloid leukemic cells". Turkish Journal of Hematology 27/1 (2010), 1-7.