Application of CXCR4 inhibitors in leukemia

Hematopoietic and cancer cells express the CXCR4 receptor, which in conjunction with its SDF-1/CXCL12 ligand mediates leukemia cell trafficking and homing to the marrow microenvironment. This interaction brings CXCR4-bearing cells within close proximity to marrow stromal cells, thus providing a niche for leukemic cell growth and contributing to drug resistance. Historically, CXCR4 antagonists were developed for the treatment of human immunodeficiency virus (HIV), but were also found to induce leukocytosis upon administration. This led to their use in hematopoietic stem cell mobilization. However, since CXCR4 plays a key role in homing and retention of normal and leukemic stem cells as well as other cancer cells to their microenvironments, the use of CXCR4 antagonists may provide for a novel therapeutic approach to interrupt these protective interactions and thus sensitize AML blasts to chemotherapy in vivo. Preclinical and/or clinical studies have shown that these novel drugs mobilize both normal hematopoietic progenitors and AML blasts into the peripheral circulation and that they are synergistic with G-CSF. In this chapter we will discuss CXCR4 inhibitors and their effects on mobilizing normal and leukemic cells when given alone or with G-CSF in preclinical models and in the clinic.