Physiology and Pharmacology of Plerixafor

Transfusion Medicine and Hemotherapy - Tập 40 Số 4 - Trang 237-245 - 2013
Simon P. Fricker1
1Sanofi-Genzyme R&D Center, Framingham, MA, USA

Tóm tắt

Autologous hematopoietic stem cell (HSC) transplantation is an important therapeutic option for patients with non-Hodgkin's lymphoma and multiple myeloma. The primary source of HSC is from the peripheral blood which requires mobilization from the bone marrow. Current mobilization regimens include cytokines such as G-CSF and/or chemotherapy. However not all patients mobilize enough HSC to proceed to transplant. The chemokine receptor CXCR4 and its ligand CXCL12 are an integral part of the mechanism of HSC retention in the bone marrow niche. The discovery of plerixafor, a selective inhibitor of CXCR4, has provided a new additional means of mobilizing HSC for autologous transplantation. Plerixafor consists of two cyclam rings with a phenylenebis(methylene) linker. It inhibits CXCL12 binding to CXCR4 and subsequent downstream events including chemotaxis. The molecular interactions of plerixafor have been defined indicating a unique binding mode to CXCR4. Plerixafor rapidly mobilizes HSC within hours compared with the multi-day treatment required by G-CSF in mouse, dog and non-human primate. The mobilized cells once transplanted are capable of timely and endurable engraftment. Additionally CXCR4 has been implicated in the pathology of HIV, inflammatory disease and cancer and the pharmacology of plerixafor in various disease models is described.

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Thông tin xuất bản

Transfusion Medicine and Hemotherapy

Tập 40 Số 4

237-245

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