title: Plerixafor (AMD3100) induces prolonged mobilization of acute lymphoblastic leukemia cells and increases the proportion of cycling cells in the blood in mice.
abstract: The CXCR4 antagonist Plerixafor (AMD3100) induces the rapid mobilization of hematopoietic stem and progenitor cells into the blood in mice and humans. AMD3100 similarly induces the mobilization of human acute lymphoblastic leukemia (ALL) cells into the blood in mice. In this study, the temporal response of pre-B ALL cells to AMD3100 was compared with that of normal hematopoietic progenitor cells (HPC) using an NOD/SCID xenograft model of ALL and BALB/c mice, respectively. ALL cells remained in the circulation up to 6 hours after AMD3100 administration, by which time normal HPCs were no longer detectable. AMD3100 also increased the proportion of actively cycling ALL cells in the peripheral blood. Together, these data suggest that ALL cells are more sensitive to the effects of bone marrow disruption than normal progenitors. Using the NOD/SCID xenograft model, we demonstrated that AMD3100 increased the efficacy of the cell cycle specific drug vincristine, resulting in reduced disease levels in the blood and spleens of animals over 3 weeks and extended the survival of NOD/SCID mice with ALL. These data demonstrate that mobilizing agents can increase the therapeutic effect of cell cycle dependent chemotherapeutic agents.
authors.affiliation: Westmead Institute for Cancer Research, Westmead Millennium Institute, University of Sydney, Westmead, New South Wales, Australia.
authors.forename: Robert
authors.initials: R
authors.lastname: Welschinger
authors.forename: Florian
authors.initials: F
authors.lastname: Liedtke
authors.forename: Jordan
authors.initials: J
authors.lastname: Basnett
authors.forename: Aileen
authors.initials: A
authors.lastname: Dela Pena
authors.forename: Julius G
authors.initials: JG
authors.lastname: Juarez
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Bradstock
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Bendall
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001596:Benzylamines; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D000080027:Cyclams; D004357:Drug Synergism; D005434:Flow Cytometry; D006410:Hematopoiesis / Q000187:drug effects; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000473:pathology / Q000628:therapy*; D019718:Receptors, CXCR4 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D014750:Vincristine; C088327:plerixafor