生物活性

• 描述Nicotinamide phosphoribosyltransferase (NAPRT) is a key enzyme in the regulation of NAD+ biosynthesis from the natural precursor nicotinamide. FK866 (Daporinad, APO866) effectively inhibited NAPRT with IC50 value of 0.09nM in a cell-free assay, which not directly inhibited mitochondrial respiratory activity, but caused gradual NAD+ depletion through specific inhibition of NAPRT. FK866 may be used for treatment of diseases implicating deregulated apoptosis such as cancer or as a sensitizer for genotoxic agents. At low concentrations ranging from 0.09-27nM, FK866 induced dose-dependent cytotoxicity in 41 hematologic malignant cells including acute myeloid leukemia, acute lymphoblastic leukemia, T-cell lymphoma and so on. While at concentrations from 0-10nM, FK866 induced cell death independent on caspase activation associated with depolarization of mitochondrial membrane. FK866 at concentrations ranging in 0-10nM also induced depletion of intracellular NAD and ATP contents and cell death in various hematologic cancer cells. Treatment with 10nM FK866 in mice with CIA, synovial inflammation was inhibited, including chemokine-directed leukocyte infiltration and serum hyaluronic acid. Besides, expression of MMP-3 and MMP-13 in joint extracts was reduced and also to a reduction in a systemic marker of cartilage erosion, serum cartilage oligomeric matrix protein. PBEF-induced secretion of MMP-3, CCL2, and CXCL8 in HFFF2 cells was reduced. FK866 was investigated in 24 patients with advanced cancers in a phase I study aiming to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD). At dose levels higher than 0.036 mg/m2/hr CTC grade III lymphocytopenia not thought to be clinically relevant, preceded all other toxicities. The recommended dose for phase II studies is 0.126 mg/m2/hr administered by civ infusion for 4 consecutive days every 4 weeks.

• 动物研究
  剂量	Rat: 0.5 mg/kg[3] (i.p.) Mice: 30 mg/kg[4] (i.p.), 100 mg/kg[5] (i.p.)
  给药途径	i.p.