alexa The AMD3100 story: the path to the discovery of a stem cell mobilizer (Mozobil).
Immunology

Immunology

Rheumatology: Current Research

Author(s): De Clercq E

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Abstract AMD3100 was found to inhibit HIV-1 and HIV-2 within the 1-10nM concentration range while not being toxic to the host cells at concentrations up to 500 microM, thus achieving a selectivity index of approximately 100,000. The target of action was initially thought to be the viral envelope glycoprotein gp120. It appeared only to be the indirect target. The direct target of action turned out to be the co-receptor CXCR4 used by T-lymphotropic HIV strains (now referred to as X4 strains) to enter the cells. Initial (phase I) clinical trials undertaken with AMD3100, as a prelude to its development as a candidate anti-HIV drug for the treatment of AIDS, showed an unexpected side effect: an increase in the white blood cell counts. Apparently, AMD3100 specifically increased CD34+ hematopoietic stem cell counts in the peripheral blood. Stromal derived factor 1 (SDF-1), through its interaction with CXCR4, retains the stem cells in the bone marrow (a process referred to as "homing"), and AMD3100 specifically antagonizes this interaction. AMD3100 in combination with granulocyte colony-stimulating factor (G-CSF) resulted in the collection of more progenitor cells than G-CSF alone. At present, the major indication for clinical use of AMD3100 (Mozobil) is the mobilization of hematopoietic stem cells from the bone marrow into the circulating blood for transplantation in patients with hematological malignancies such as non-Hodgkin's lymphoma or multiple myeloma. This article was published in Biochem Pharmacol and referenced in Rheumatology: Current Research

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