Antiviral Mediated Apoptosis of Non-Hodgkin's Lymphoma

描述（由申请人提供）：免疫功能低下患者的淋巴增生性疾病治疗是有问题的。这些患者通常对细胞毒性药物反应不佳，这也加重了他们潜在的免疫抑制。尽管如此，这些肿瘤有不同的病理生理特征，可以作为治疗靶点。这些淋巴瘤通常与γ疱疹病毒有关，并依赖于nf - κ b的组成性表达。我们已经确定了一种新的促凋亡疗法，用于治疗人类疱疹病毒8型（HHV-8）、原发性渗出性淋巴瘤（PEL）和eb病毒淋巴瘤（EBV）。Azidothymidine （AZT）和干扰素α诱导死亡受体配体介导的PEL细胞凋亡。这是通过干扰素介导的配体TRAIL的有效激活以及AZT对NF-kappaB的抑制而发生的。我们假设死亡受体信号在NF-kappaB依赖性抗凋亡因子的抑制下被增强。NF-kappaB阻断是由单磷酸形式的AZT影响的，AZT优先在HHV-8和EBV相关淋巴瘤中产生。我们已经在动物模型和患者中证明了抗病毒治疗对伽玛疱疹病毒相关淋巴瘤的有效性。我们建议通过以下途径来研究介导这种凋亡的细胞和病毒因子：1)确定疱疹病毒淋巴瘤中抗病毒药物诱导的信号转导通路；2)确定细胞和病毒蛋白（如vFlip）在NF-kappaB介导的死亡受体介导的细胞凋亡阻断中的作用；3)研究病毒胸腺嘧啶激酶在抗病毒胸腺嘧啶类似物磷酸化和细胞凋亡起始中的作用；4)在新建立的SCID小鼠模型中研究抗病毒药物的抗淋巴瘤作用。开发一种基于抗病毒治疗的治疗策略将代表一种针对资源贫乏地区淋巴瘤的靶向生物学方法。

DESCRIPTION (provided by applicant): Therapy for lymphoproliferative disease in immunocompromised patients is problematic. These patients often have a poor response to cytotoxic agents that also worsens their underlying immunosuppression. Nonetheless, there are distinct pathophysiologic features of these tumors that may be exploited as therapeutic targets. These lymphomas are often associated with gamma herpesviruses and dependent upon constitutive expression of NF-kappaB. We have identified a novel, pro-apoptotic therapy for Humanherpes Virus Type 8 (HHV-8), Primary Effusion Lymphoma (PEL) and Epstein Barr Virus (EBV) lymphomas. Azidothymidine (AZT) and Interferon alpha induce death receptor ligand mediated apoptosis in PEL. This occurs through a potent activation of the ligand TRAIL mediated by interferon alpha coupled with suppression of NF-kappaB by AZT. We hypothesize that death receptor signaling is potentiated upon suppression of NF-kappaB dependent anti-apoptotic factors. NF-kappaB blockade is effected by the monophosphate form of AZT which is preferentially generated in HHV-8 and EBV associated lymphomas. We have demonstrated the effectiveness of antiviral therapy for gamma herpesvirus associated lymphomas in both animal models and patients. We propose to investigate the cellular and viral factors that mediate this apoptosis by 1) defining the signal transduction pathways induced by antivirals in herpesvirus lymphomas; 2) determining the role of cellular and viral proteins (such as vFlip) in NF-kappaB mediated blockade of death receptor mediated apoptosis; 3) investigating the role of viral thymidine kinase in the phosphorylation of antiviral thymidine analogues and the initiation of apoptosis and; 4) studying the anti-lymphoma effects of antivirals in a recently developed SCID mouse model. Development of a therapeutic strategy based on antiviral therapy would represent a targeted, biological approach to lymphomas in resource poor settings.