CXCR4 antagonists mobilize childhood acute lymphoblastic leukemia cells into the peripheral blood and inhibit engraftment.
The role of CXCL12 in the bone marrow (BM) homing and growth of B-cell progenitor acute lymphoblastic leukemia (ALL) has been established. However, the effect of modulating CXCL12/CXCR4 interactions on the retention of ALL cells within the supportive BM microenvironment and the expansion and dissemination of ALL cells in vivo has not been examined. We used mouse models of human childhood and murine leukemia and specific peptide and small molecule CXCR4 antagonists to examine the importance of CXCL12/CXCR4 in the development of leukemia in vivo. CXCR4 antagonists mobilized ALL cells into the peripheral blood (PB). Extended administration of CXCR4 antagonists to mice with leukemia resulted in a reduction in the number of leukemic cells in the PB and spleens of animals compared to control treated animals in three of the five cases tested. There was also a marked reduction in the dissemination of ALL cells to extramedullary sites including liver and kidney in all cases where this occurred. Considering the inhibitory effect of stromal layers on the activity of chemotherapeutic agents and the interactive effect of CXCL12 antagonists with chemotherapeutic agents in vitro, this raises the possibility of using these agents to potentiate the effects of current chemotherapy regimens.
Juarez
J
J
1Westmead Institute for Cancer Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia.
Dela Pena
A
A
Baraz
R
R
Hewson
J
J
Khoo
M
M
Cisterne
A
A
Fricker
S
S
Fujii
N
N
Bradstock
K F
KF
Bendall
L J
LJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001769:Blood; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors; D002633:Chemotaxis / Q000187:drug effects*; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D004347:Drug Interactions; D005260:Female; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009360:Neoplastic Cells, Circulating / Q000187:drug effects*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D013154:Spleen; D017154:Stromal Cells; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4