NS1 protein of influenza virus is a virulence factor that counteracts Type I interferon (IFN)- Key words: conditionally-replicating-virus; STAT1; SCIDKnowledge of the pathogenesis of viral diseases and the ability to manipulate specific regions of viral genomes permit the construction of conditionally replicating viruses that are attenuated in normal cells but retain their ability to lyse tumor cells. [1][2][3] We show that the NS1 protein of influenza A virus is a virulence factor that counteracts the interferon (IFN)-mediated antiviral cellular response. 4 As a consequence, an influenza virus that lacks a functional NS1 protein due to an almost total deletion of the NS1 open reading frame (delNS1 virus) fails to replicate in normal cells and is apathogenic for wild-type mice. 5 The delNS1 virus, however, grows to titers similar to wild-type virus in dsRNA-activated kinase (PKR) knockout mice. 6 The conditionally replicating phenotype of the delNS1 virus in PKR-defective systems could be exploited for virally-induced oncolysis in tumors expressing oncogenic ras. 7 This observation is based on the fact that oncogenic ras inhibits PKR activation. 8 For this reason, melanoma cells became permissive for productive delNS1 virus replication upon transfection and expression of oncogenic N-ras. Moreover, delNS1 virus treatment of subcutaneous N-ras-expressing melanomas in SCID mice showed that this virus has tumor-ablative potentials in vivo.The delNS1 virus was also shown to replicate effectively in STAT1 knockout mice. 9 STAT1 exists in 2 isoforms, a 91-kD protein (STAT1␣) and a 84-kD splice variant (STAT1). 10 Upon activation by Type I IFN signaling STAT1 forms a heterodimer with STAT2 and becomes an essential part of the IFN-receptor induced transcription complex ISGF3. A reduced expression of STAT1 is associated with IFN resistance. 11 Alterations in the IFN-dependent signal cascades, including changes in STAT1 and Type I IFN-receptor molecules, have been described to occur frequently in malignantly transformed cells. For example, several melanoma and lymphoma cell lines contain no or reduced levels of STAT1. 12,13 In addition, leukemia cell lines were shown to be defective in IFN genes. 14 We hypothesized, therefore, that IFN resistance is a common tumor characteristic, which may allow delNS1 virus-mediated oncolysis.We analyzed the growth of delNS1 virus in IFN-resistant tumor cell lines of various histological origins. We compared the oncolytic effect of the delNS1 virus with a second virus, in which the NS1 was only deleted to the N-terminal 99 amino acids (NS1-99). In mice, the latter virus has intermediate attenuation properties ranging between delNS1 and wild-type viruses. 15 The NS1-99 virus gave us the possibility to investigate whether the attenuation level of NS1-deletion viruses influences the efficiency of oncolysis in vivo. The in vitro growth of the NS1-deletion mutants inversely correlated with the IFN resistance of the assayed cell lines. Both delNS1 and NS1-99 viruses induced a tumor-ablative ef...
Background: With current treatment strategies, nearly half of all medulloblastoma (MB) patients die from progressive tumors. Accordingly, the identification of novel therapeutic strategies remains a major goal. Deregulation of c-MYC is evident in numerous human cancers. In MB, over-expression of c-MYC has been shown to correlate with anaplasia and unfavorable prognosis. In neuroblastoma -an embryonal tumor with biological similarities to MB -the quassinoid NBT-272 has been demonstrated to inhibit cellular proliferation and to downregulate c-MYC protein expression.
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