A CXCR4 receptor antagonist
AMD 3465 hexahydrobromide is a potent antagonist of CXCR4, inhibits binding of 12G5 mAb and CXCL12AF647 to CXCR4, with IC50s of 0.75 nM and 18 nM in SupT1 cells; AMD 3465 also potently inhibits the replication of X4 HIV strains (IC50: 1-10 nM), but has no effect on CCR5-using (R5) viruses.
AMD 3465 hexahydrobromide is a potent antagonist of CXCR4, inhibits binding of 12G5 mAb and CXCL12AF647 to CXCR4, with IC50s of 0.75 nM and 18 nM in SupT1 cells. AMD 3465 (50 nM) totally blocks CXCL12-induced calcium mobilization, with an IC50 of 17 nM, but shows no effect on the intracellular calcium fluxes elicited by the CCR5 ligands RANTES, LD78β and MIP-1β in U87.CD4.CCR5 cells. AMD 3465 also potently inhibits the replication of X4 HIV strains (IC50: 1-10 nM), but has no effect on CCR5-using (R5) viruses. AMD3465 is cytotoxic to the X4 HIV-1 strains IIIB, NL4.3, RF and HE with an IC50 ranging from 6 to 12 nM. The IC50 for suppression of the HIV-2 strains ROD and EHO is 12.3 nM[1]. AMD 3465 inhibits CXCL-12-induced growth in U87 and Daoy cells. AMD 3465 treatment stimulates the phosphorylation of Erk1/2 in U87 and Daoy cells[2].
AMD 3465 (2.5 mg/kg/d, s.c. for 5 weeks) significantly blocks the growth of U87 GBM and Daoy xenografts[2].
参考文献:
[1]. Hatse S, et al. AMD3465, a monomacrocyclic CXCR4 antagonist and potent HIV entry inhibitor. Biochem Pharmacol. 2005 Sep 1;70(5):752-61.
[2]. Yang L, et al. Blocking CXCR4-mediated cyclic AMP suppression inhibits brain tumor growth in vivo. Cancer Res. 2007 Jan 15;67(2):651-8.
Cell experiment: | Following serum starvation for 24 h, astrocytes, granule cells, U87 cells, and Daoy cells are treated with 1 μg/mL CXCL12, 2.5 ng/mL AMD 3465, 200 μM rolipram, or 10 μM forskolin. Daoy and U87 cell growth in culture is measured by trypan blue exclusion after 24 and 48 h of treatment, respectively[2]. |
Animal experiment: | Mice[2]Mice are imaged at least twice after implantation of cells to identify those with equivalent tumor growth rates. Two weeks after tumor cell implantation, cohorts of mice with approximately equivalent tumor bioluminescence are divided into equal control and treatment groups. Animals in AMD 3465 experiments receive s.c. osmotic pumps loaded with 10 mg/mL AMD 3465 in sterile PBS or PBS alone. The infusion rate is 0.25 μL/h (50 μg/d). For the experiments with rolipram or caffeine, mice in the treatment groups receive oral administration of rolipram (5 μg/g/d) or caffeine (100 μg/g/d). The concentration of drug in the water is determined from daily measurements of water consumption by each animal over the course of 7 days. Concentrations are adjusted based on water consumption to provide the prescribed dose[2]. |
参考文献: [1]. Hatse S, et al. AMD3465, a monomacrocyclic CXCR4 antagonist and potent HIV entry inhibitor. Biochem Pharmacol. 2005 Sep 1;70(5):752-61. | |
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