Synthesis and evaluation of CXCR2 antagonists on the survival of primary acute lymphoblastic leukemia in co-culture with bone marrow stromal cells.

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Acute lymphoblastic leukemia (ALL) is the most frequent childhood malignancy. host factors play an important role in the development of ALL. Among them, de novo angiogenesis, i.e. the formation of novel blood vessels, has recently been associated with ALL. Microarray results of in vitro co-culturing experiments revealed several Bone Marrow Endothelial Cell genes which are induced/repressed by ALL cells or plasma. One of these leukemia-induced genes was interleukin-8 (IL-8), a cytokine already implicated with the clinical evolution of some type of leukemia. To explore the effect of IL-8 in the ALL bone marrow microenvironment, we synthesized a CXCR2 (IL-8 receptor) antagonist called SB225002 (N-(2-hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea). ALL cells from 12 patients were co-cultured with BM stromal cell and increasing amounts of SB225002. Intriguingly, for some of the patients cells, blocking the IL-8 receptor by SB225002 seems to increase ALL survival after 48h of coculture. New SB225002 analogs were synthesized and are under test. Support: CNPq, FAPESP