1. ¹Westmead Institute for Cancer Research, Westmead Millennium Institute, University of Sydney, Australia
2. ²Department of Hematology Westmead Hospital, Australia
3. ³Department of Medicine, University of Sydney, Australia

Correspondence: Dr LJ Bendall, Westmead Institute for Cancer Research, Westmead Millennium Institute, Westmead Hospital, Westmead, NSW 2145, Australia. Fax: +61 2 9845 9102

Received 2 December 2002; Accepted 17 March 2003.

Abstract

Stromal cell-derived factor-1 (SDF-1) is a key regulator of the behavior of normal and leukemic precursor-B (pre-B) cells. It is possible that inhibiting SDF-1-driven processes in pre-B acute lymphoblastic leukemia (ALL) may have therapeutic implications. In this study, we examined the ability of SDF-1 inhibitors to modulate pre-B ALL cell responses to SDF-1, including chemotaxis, migration into bone marrow stroma, and stroma-supported survival and proliferation on human bone marrow stromal layers. The polyphemusin II-derived inhibitors, T140, TC140012, and T134, and the bicyclam AMD3100, effectively inhibited binding of the anti-CXCR4 monoclonal antibody 12G5 on the pre-B ALL cell line NALM6, with IC₅₀ values of 0.9, 0.9, 0.9, and 1.9 nM, respectively. Similar results were obtained with ALL samples. T140 (0.1 M) and AMD3100 (1 M) completely blocked SDF-1-induced chemotaxis and attenuated the migration of pre-B ALL cells into bone marrow stromal layers. AMD3100 and TC140012 at a concentration of 50 M significantly inhibited stroma-dependent proliferation of six and four of the eight cases tested, respectively, without reducing the cell viability. In addition, AMD3100 and TC140012 enhanced the cytotoxic and antiproliferative effects of the cytotoxic agents vincristine and dexamethasone. The ability of SDF-1 inhibitors to modulate these biologically important functions of leukemic cells warrants further investigation.