Disease relevance of SID791

• AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor [1].
• AMD3100 also mobilized murine long-term repopulating (LTR) cells that engrafted primary and secondary lethally-irradiated mice, and human CD34(+) cells that can repopulate nonobese diabetic-severe combined immunodeficiency (SCID) mice [2].
• AMD3100, a CXCR4 antagonist, was active against HIV-2 and SHIV89.6, a finding consistent with the use of the CXCR4 co-receptor by these isolates, but was inactive against SIV strains [3].
• AMD3100 was well tolerated and caused only mild, transient toxicity [4].
• Collectively, these data suggest that monocytes mobilized into the blood by G-CSF or AMD3100 stimulate angiogenesis at sites of ischemia through a paracrine mechanism [5].

High impact information on SID791

• Thus, AMD3100 prevents CXCR4 functioning as both a HIV-1 co-receptor and a CXC-chemokine receptor [1].
• AMD3100 prevents monoclonal antibody 12G5 from binding to CXCR4, but has no effect on binding of monoclonal antibody 2D7 to CCR5 [1].
• AMD3100, a selective antagonist of CXCL12 that binds to its receptor, CXCR4, was evaluated in murine and human systems for mobilizing capacity, alone and in combination with granulocyte colony-stimulating factor (G-CSF) [2].
• Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist [2].
• Human CD34(+) cells isolated after treatment with G-CSF plus AMD3100 expressed a phenotype that was characteristic of highly engrafting mouse HSCs [2].

Chemical compound and disease context of SID791

• The bicyclam AMD3100 is a potent and selective inhibitor of the replication of human immunodeficiency virus type 1 and type 2 (HIV-1 and HIV-2) [6].
• When primary FIV isolates were evaluated for their drug susceptibility in feline thymocytes, the bicyclams AMD3100 and its Zn2+ complex, AMD3479, inhibited all six primary isolates at equal potency [7].
• The prototype, JM3100 (19a, isolated as the octahydrochloride salt), which contains a p-phenylenebis(methylene) moiety linking the cyclam rings, inhibited the replication of HIV-1 (IIIB) and HIV-2 (ROD) at EC50's of 4.2 and 5.9 nM, respectively, while remaining nontoxic to MT-4 cells at concentrations exceeding 421 microM [8].
• HIV-1 strains resistant to two prototype bicyclams, JM2763 and SID791 (JM3100), were raised [9].

Biological context of SID791

• The kinetics of angiogenic-cell mobilization by these agents appears to be distinct, with more rapid revascularization observed in AMD3100-treated mice [5].
• Peripheral-blood mononuclear cells (PBMCs) mobilized with AMD3100, a CXCR4 antagonist, combined with granulocyte colony-stimulating factor (G-CSF) have reconstituted autologous hematopoiesis in cancer patients following myeloablative conditioning [10].
• The chemokine CXCL12 induced chemotaxis in CXCR4-positive pancreatic carcinoma cell lines, which was inhibited by anti-CXCR4 monoclonal antibody and by the antagonist AMD3100 [11].
• The absolute CD34+ cell counts observed at 4 and 6 hours following AMD3100 were higher in the 240 microg/kg group (19.3 +/- 6.9/microL and 20.4 +/- 7.6/microL, respectively) compared with the 160 microg/kg group (11.3 +/- 2.7/microL and 11.3 +/- 2.5/microL, respectively) [12].
• Metal ion binding in the cyclam rings of AMD3100 increased its dependence on Asp(262) and provided a tighter molecular map of the binding site, where borderline mutational hits became clear hits for the Zn(II)-loaded analog [13].

Anatomical context of SID791

• We show engraftment of transduced AMD3100-mobilized CD34(+) cells with Neo(R) gene marked myeloid and lymphoid cells up to 32 months after transplantation, demonstrating the ability of AMD3100 to mobilize true long-term repopulating hematopoietic stem cells [14].
• G-CSF and AMD3100 mobilize monocytes into the blood that stimulate angiogenesis in vivo through a paracrine mechanism [5].
• Combination treatment with G-CSF and AMD3100 resulted in the earliest and most complete recovery in blood flow to the ischemic hindlimb [5].
• The cell line Hs766T produces high levels of CXCL12, and addition of the CXCR4 antagonist AMD3100 partially inhibited proliferation, indicating an autocrine loop [11].
• We also showed that AMD3100 (a specific CXCR4 antagonist) effectively reduced tumor growth and ascitic fluid formation in nude mice inoculated with NUGC4 cells [15].

Associations of SID791 with other chemical compounds

• The discovery and development of the bicyclam AMD3100 highlighted the clinical potential of such compounds in AIDS, cancer and stem-cell mobilization [16].
• The effects of AMD3100, alone or in combination with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), on cell growth were determined for several of these cell lines in vitro [17].
• Studies using TAK-779 and AMD3100 showed that two highly M-tropic isolates entered microglia primarily via CXCR4 [18].
• AMD3451, in contrast to the specific CXCR4 antagonist AMD3100, did not inhibit but enhanced the binding of several anti-CXCR4 monoclonal antibodies (such as clone 12G5) at the cell surface, pointing to a different interaction with CXCR4 [19].
• AMD3329 also inhibited the binding of a specific CXCR4 mAb and the Ca(2+) flux induced by SDF-1alpha, the natural ligand for CXCR4, more potently than AMD3100 [20].

Gene context of SID791

• AMD3100 dose dependently inhibited the binding of a specific CXCR4 monoclonal antibody to SUP-T1 cells as measured by flow cytometry [21].
• CXCL12 increased the growth in PES 41, PES 43, and PES 47 cells under suboptimal (1% serum) and serum-free culture conditions; AMD3100 (1 mumol/L) inhibited the spontaneous and CXCL12-induced proliferation [22].
• Several strains replicated in Delta32/Delta32 CCR5 PBMCs with CXCR4 blocked by AMD3100 [23].
• It was insensitive to eotaxin, vMIP-1 and I309 when tested individually, but was inhibited completely when vMIP-1 or I309 was combined with AMD3100 [24].
• Early recruitment of adoptively transferred OVA-specific CTL into B16/OVA tumors expressing high levels of CXCL12 was significantly reduced in comparison to B16/OVA tumors, and this reduction was reversed when tumor-specific CTLs were pretreated with the specific CXCR4 antagonist, AMD3100 [25].

Analytical, diagnostic and therapeutic context of SID791

• In addition, mobilization with AMD3100 may provide a safer preparative approach for HSC transplantation in genetic and other nonmalignant disorders [26].
• These data show that AMD3100 is a potent and rapid mobilizer of angiogenic cells and demonstrate the feasibility of obtaining and storing large numbers of angiogenic cells by leukapheresis [27].
• We investigated whether AMD3100, a selective CXCR4 antagonist, could mobilize hematopoietic progenitor cells from marrow to peripheral blood in healthy human volunteers [4].
• CONCLUSION: AMD3100 appears to be a safe and effective agent for the rapid mobilization of CD34+ cells in patients who have received prior chemotherapy [12].
• The small-molecule-mobilising drug AMD3100 was selected because mobilisation and apheresis can be done on the same day [28].

References