Colony-stimulating-factor-1 (CSF-1) signaling through cFMS receptor kinase is increased in several diseases. To help investigate the role of cFMS kinase in disease, we identified GW2580, an orally bioavailable inhibitor of cFMS kinase. GW2580 completely inhibited human cFMS kinase in vitro at 0.06 M and was inactive against 26 other kinases. GW2580 at 1 M completely inhibited CSF-1-induced growth of mouse M-NFS-60 myeloid cells and human monocytes and completely inhibited bone degradation in cultures of human osteoclasts, rat calvaria, and rat fetal long bone. In contrast, GW2580 did not affect the growth of mouse NS0 lymphoblastoid cells, human endothelial cells, human fibroblasts, or five human tumor cell lines. GW2580 also did not affect lipopolysaccharide (LPS)-induced TNF, IL-6, and prostaglandin E2 production in freshly isolated human monocytes and mouse macrophages. After oral administration, GW2580 blocked the ability of exogenous CSF-1 to increase LPS-induced IL-6 production in mice, inhibited the growth of CSF-1-dependent M-NFS-60 tumor cells in the peritoneal cavity, and diminished the accumulation of macrophages in the peritoneal cavity after thioglycolate injection. Unexpectedly, GW2580 inhibited LPS-induced TNF production in mice, in contrast to effects on monocytes and macrophages in vitro. In conclusion, GW2580's selective inhibition of monocyte growth and bone degradation is consistent with cFMS kinase inhibition. The ability of GW2580 to chronically inhibit CSF-1 signaling through cFMS kinase in normal and tumor cells in vivo makes GW2580 a useful tool in assessing the role of cFMS kinase in normal and disease processes.CSF-1 ͉ macrophage colony-stimulating factor
Hepatitis B viruses establish a chronic, productive, and noncytopathic infection of hepatocytes. Viral products are produced by transcription from multiple copies (5-50) of covalently closed circular (ccc) viral DNA. This cccDNA does not replicate, but can be replaced by DNA precursors that are synthesized in the cytoplasm. The present study was carried out to determine if long-term treatment with an inhibitor of viral DNA synthesis would lead to loss of virus products, including cccDNA, from the liver of woodchucks chronically infected with woodchuck hepatitis virus. Viral DNA synthesis was inhibited with the nucleoside analog, lamivudine (2'-deoxy-3'-thiacytidine). Lamivudine treatment produced a slow but progressive decline in viral titers in serum, to about 0.3% or less of the initial level. However, even after maintenance of drug therapy for 3-12 months, > 95% of the hepatocytes in most animals were still infected. Significant declines in the percentage of infected hepatocytes and of intrahepatic cccDNA levels were observed in only three woodchucks, two in the group receiving lamivudine and one in the placebo control group. Moreover, virus titers eventually rose in woodchucks receiving lamivudine, suggesting that drug-resistant viruses began to spread through the liver starting at least as early as 9-12 months of treatment. Three types of mutation that may be associated with drug resistance were found at this time, in a region upstream of the YMDD motif in the active site of the viral reverse transcriptase. The YMDD motif itself remained unchanged. Not unexpectedly, the lamivudine therapy did not have a impact on development of liver cancer.
The anti-hepatitis B (anti-HBV) activities of the (-) and (+) enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine (2'-deoxy-3'-thia-5-fluorocytosine [FTC]) were studied by using an HBVtransfected cell line (HepG2 derivative 2.2.15, subclone P5A). The (-) isomer was found to be a potent inhibitor of viral replication, with an apparent 50% inhibitory concentration of 10 nM, whfle the (+) isomer was found to be considerably less active. Both isomers showed miimal toxicity to HepG2 cells (50% inhibitory concentration, >200 a.M) and showed minimal toxicity in the human bone marrow progenitor cell assay. In accord with the cellular antiviral activity data, the 5'-triphosphate of (-)-FIC inhibited viral DNA synthesis in an endogenous HBV DNA polymerase assay, while the 5'-triphosphate of the (+) isomer was inactive.Unphosphorylated (-)-FTC did not inhibit product formation in the endogenous assay, souggestng that the antiviral activity of the compound is dependent on anabolism to the 5'-triphosphate. Both (-)-and (+)-FTC were anabolized to the corresponding 5'-triphosphates in chronically HBV-infected HepG2 celLs. The rate of accumulation and the steady-state concentration of the 5'-triphosphate of (-)-FTC were greater. Also, (-)-FTC was not a substrate for cytidine deaminase and, therefore, is not subject to d tion and conversion to an inactive uridine analog. The (+) isomer is, however, a good substrate for cytidine deaminase.Hepatitis B virus (HBV), the causative agent of acute and chronic hepatitis, directly affects about 5% of the world's population. Chronic carriers of HBV are at an increased risk of liver damage that, in the worst cases, can lead to cirrhosis of the liver and/or to hepatocellular carcinoma. Vaccination against HBV is one way to effectively prevent HBV infection. However, vaccination is not an effective therapy for the estimated 200 million chronic carriers. Although several antiviral agents such as alpha interferon, adenine arabinoside monophosphate, and acyclovir have been tested as therapeutic agents, only alpha interferon has demonstrated some promise (7,8,9,17,23,25).The replication cycle of hepadnaviruses includes the reverse transcription of an RNA template (6). This process is catalyzed by a polymerase that shares significant sequence homology with the reverse transcriptase from retroviruses (17). As a consequence, it has been demonstrated that a number of compounds that inhibit human immunodeficiency virus (HIV) replication in vitro (for example, 2',3'-dideoxycytidine) also inhibit HBV replication in vitro (4,14,15,18,24). These agents await further study to determine their usefulness as therapeutic agents for the treatment of HBV infections.Here we report the anti-HBV activities, cytotoxicities, and anabolism of the resolved enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine (FTC) (Fig. 1). The anti-HBV activity of the racemic material has been reported previously (4). Our results show that the * Corresponding authors. antiviral activ...
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