Antiviral Mediated Apoptosis of Non-Hodgkin's Lymphoma

描述（由申请人提供）：免疫功能低下患者淋巴组织增生性疾病的治疗存在问题。这些患者通常对细胞毒性药物的反应较差，这也导致了其潜在的免疫抑制。尽管如此，这些肿瘤有不同的病理生理学特征，可作为治疗靶点。这些淋巴瘤通常与γ疱疹病毒相关，并依赖于NF-κ B的组成型表达。我们已经确定了一种新的，促细胞凋亡治疗人类疱疹病毒8型（HHV-8），原发性efflymphoma（PEL）和爱泼斯坦巴尔病毒（EBV）淋巴瘤。叠氮胸苷（AZT）和干扰素α诱导PEL中死亡受体配体介导的凋亡。这是通过α干扰素介导的配体TRAIL的有效激活以及AZT对NF-κ B的抑制而发生的。我们假设，死亡受体信号转导是加强后，抑制NF-κ B依赖性抗凋亡因子。NF-kappaB阻断受AZT单磷酸盐形式的影响，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γ疱疹病毒相关淋巴瘤的有效性。我们建议调查介导这种细胞凋亡的细胞和病毒因素，1）确定抗病毒药物诱导的疱疹病毒淋巴瘤的信号转导途径，2）确定细胞和病毒蛋白的作用，（如vFlip）在NF-κ B介导的阻断死亡受体介导的细胞凋亡中的作用; 3）研究病毒胸苷激酶在抗病毒胸苷类似物磷酸化和细胞凋亡启动中的作用; 4）在最近开发的SCID小鼠模型中研究抗病毒药物的抗淋巴瘤作用。基于抗病毒治疗的治疗策略的发展将代表资源贫乏环境中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.