Combination of Drug Therapy in Acute Lymphoblastic Leukemia with a CXCR4 Antagonist

Overview

Journal Leukemia

Specialties Hematology
Oncology

Date 2011 Apr 13

PMID 21483439

Citations 38

Authors

R Parameswaran

M Yu

M Lim

J Groffen

N Heisterkamp

Affiliations

Soon will be listed here.

Abstract

The bone marrow (BM) stromal niche can protect acute lymphoblastic leukemia (ALL) cells against the cytotoxicity of chemotherapeutic agents and is a possible source of relapse. The stromal-derived factor-1 (SDF-1)/CXCR4 axis is a major determinant in the crosstalk between leukemic cells and BM stroma. In this study, we investigated the use of AMD11070, an orally available, small-molecule antagonist of CXCR4, as an ALL-sensitizing agent. This compound effectively blocked stromal-induced migration of human ALL cells in culture and disrupted pre-established adhesion to stroma. To examine how to optimally use this compound in vivo, several combinations with cytotoxic drugs were tested in a stromal co-culture system. The best treatment regimen was then tested in vivo. Mice transplanted with murine Bcr/Abl ALL cells survived significantly longer when treated with a combination of nilotinib and AMD11070. Similarly, immunocompromised mice transplanted with human ALL cells and treated with vincristine and AMD11070 had few circulating leukemic cells, normal spleens and reduced human CD19+ cells in the BM at the termination of the experiment. These results show that combined treatment with AMD11070 may be of significant benefit in eradicating residual leukemia cells at locations where they would otherwise be protected by stroma.

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References

Fullmer A, OBrien S, Kantarjian H, Jabbour E . Novel therapies for relapsed acute lymphoblastic leukemia. Curr Hematol Malig Rep. 2010; 4(3):148-56. PMC: 4572835. DOI: 10.1007/s11899-009-0021-6. View

Scala S, Ottaiano A, Ascierto P, Cavalli M, Simeone E, Giuliano P . Expression of CXCR4 predicts poor prognosis in patients with malignant melanoma. Clin Cancer Res. 2005; 11(5):1835-41. DOI: 10.1158/1078-0432.CCR-04-1887. View

Wang J, Wang J, Sun Y, Song W, Nor J, Wang C . Diverse signaling pathways through the SDF-1/CXCR4 chemokine axis in prostate cancer cell lines leads to altered patterns of cytokine secretion and angiogenesis. Cell Signal. 2005; 17(12):1578-92. DOI: 10.1016/j.cellsig.2005.03.022. View

Glodek A, Le Y, Dykxhoorn D, Park S, Mostoslavsky G, Mulligan R . Focal adhesion kinase is required for CXCL12-induced chemotactic and pro-adhesive responses in hematopoietic precursor cells. Leukemia. 2007; 21(8):1723-32. DOI: 10.1038/sj.leu.2404769. View

Fei F, Stoddart S, Groffen J, Heisterkamp N . Activity of the Aurora kinase inhibitor VX-680 against Bcr/Abl-positive acute lymphoblastic leukemias. Mol Cancer Ther. 2010; 9(5):1318-27. PMC: 2868097. DOI: 10.1158/1535-7163.MCT-10-0069. View

Ara T, Itoi M, Kawabata K, Egawa T, Tokoyoda K, Sugiyama T . A role of CXC chemokine ligand 12/stromal cell-derived factor-1/pre-B cell growth stimulating factor and its receptor CXCR4 in fetal and adult T cell development in vivo. J Immunol. 2003; 170(9):4649-55. DOI: 10.4049/jimmunol.170.9.4649. View

Devine S, Flomenberg N, Vesole D, Liesveld J, Weisdorf D, Badel K . Rapid mobilization of CD34+ cells following administration of the CXCR4 antagonist AMD3100 to patients with multiple myeloma and non-Hodgkin's lymphoma. J Clin Oncol. 2004; 22(6):1095-102. DOI: 10.1200/JCO.2004.07.131. View

Zeng Z, Shi Y, Samudio I, Wang R, Ling X, Frolova O . Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML. Blood. 2008; 113(24):6215-24. PMC: 2699240. DOI: 10.1182/blood-2008-05-158311. View

Drummond M, Heaney N, Kaeda J, Nicolini F, Clark R, Wilson G . A pilot study of continuous imatinib vs pulsed imatinib with or without G-CSF in CML patients who have achieved a complete cytogenetic response. Leukemia. 2009; 23(6):1199-201. DOI: 10.1038/leu.2009.43. View

10.

Baersch G, Mollers T, Hotte A, Dockhorn-Dworniczak B, Rube C, Ritter J . Good engraftment of B-cell precursor ALL in NOD-SCID mice. Klin Padiatr. 1997; 209(4):178-85. DOI: 10.1055/s-2008-1043947. View

11.

Bradstock K, Makrynikola V, Bianchi A, Shen W, Hewson J, Gottlieb D . Effects of the chemokine stromal cell-derived factor-1 on the migration and localization of precursor-B acute lymphoblastic leukemia cells within bone marrow stromal layers. Leukemia. 2000; 14(5):882-8. DOI: 10.1038/sj.leu.2401729. View

12.

Geminder H, Sagi-Assif O, Goldberg L, Meshel T, Rechavi G, Witz I . A possible role for CXCR4 and its ligand, the CXC chemokine stromal cell-derived factor-1, in the development of bone marrow metastases in neuroblastoma. J Immunol. 2001; 167(8):4747-57. DOI: 10.4049/jimmunol.167.8.4747. View

13.

Kaur P, Feldhahn N, Zhang B, Trageser D, Muschen M, Pertz V . Nilotinib treatment in mouse models of P190 Bcr/Abl lymphoblastic leukemia. Mol Cancer. 2007; 6:67. PMC: 2169263. DOI: 10.1186/1476-4598-6-67. View

14.

Dillmann F, Veldwijk M, Laufs S, Sperandio M, Calandra G, Wenz F . Plerixafor inhibits chemotaxis toward SDF-1 and CXCR4-mediated stroma contact in a dose-dependent manner resulting in increased susceptibility of BCR-ABL+ cell to Imatinib and Nilotinib. Leuk Lymphoma. 2009; 50(10):1676-86. DOI: 10.1080/10428190903150847. View

15.

Crazzolara R, Kreczy A, Mann G, Heitger A, Eibl G, Fink F . High expression of the chemokine receptor CXCR4 predicts extramedullary organ infiltration in childhood acute lymphoblastic leukaemia. Br J Haematol. 2001; 115(3):545-53. DOI: 10.1046/j.1365-2141.2001.03164.x. View

16.

Orimo A, Gupta P, Sgroi D, Arenzana-Seisdedos F, Delaunay T, Naeem R . Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005; 121(3):335-48. DOI: 10.1016/j.cell.2005.02.034. View

17.

Jemal A, Tiwari R, Murray T, Ghafoor A, Samuels A, Ward E . Cancer statistics, 2004. CA Cancer J Clin. 2004; 54(1):8-29. DOI: 10.3322/canjclin.54.1.8. View

18.

Manabe A, Murti K, Coustan-Smith E, Kumagai M, Behm F, Raimondi S . Adhesion-dependent survival of normal and leukemic human B lymphoblasts on bone marrow stromal cells. Blood. 1994; 83(3):758-66. View

19.

Gaynon P . Childhood acute lymphoblastic leukaemia and relapse. Br J Haematol. 2005; 131(5):579-87. DOI: 10.1111/j.1365-2141.2005.05773.x. View

20.

Stone N, Dunaway S, Flexner C, Tierney C, Calandra G, Becker S . Multiple-dose escalation study of the safety, pharmacokinetics, and biologic activity of oral AMD070, a selective CXCR4 receptor inhibitor, in human subjects. Antimicrob Agents Chemother. 2007; 51(7):2351-8. PMC: 1913234. DOI: 10.1128/AAC.00013-07. View