Antiviral Mediated Apoptosis of Non-Hodgkin's Lymphoma

描述(由申请人提供)：免疫受损患者的淋巴增生性疾病的治疗是有问题的。这些患者对细胞毒性药物的反应通常很差，这也加剧了他们潜在的免疫抑制。尽管如此，这些肿瘤有明显的病理生理特征，可以作为治疗的靶点。这些淋巴瘤通常与伽马疱疹病毒相关，并依赖于NF-kappaB的结构性表达。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(EBV)淋巴瘤。叠氮胸苷(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α介导的配体TRAIL的有效激活和AZT抑制核因子-kappaB来实现的。我们假设死亡受体信号在抑制依赖于核因子-kappaB的抗凋亡因子后被增强。核因子-kappaB的阻断受单磷酸形式的AZT的影响，这种形式的AZT在HHV-8和EBV相关的淋巴瘤中优先产生。我们已经在动物模型和患者中证明了抗病毒治疗对伽马疱疹病毒相关淋巴瘤的有效性。我们建议通过以下方式研究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疱疹病毒淋巴瘤的信号转导通路；2)确定细胞和病毒蛋白(如vFlip)在核因子-kappaB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启动细胞凋亡中的作用；4)在最近建立的SCID小鼠模型中研究抗病毒药物的抗淋巴瘤作用。以抗病毒治疗为基础的治疗策略的开发将代表着在资源匮乏的情况下对淋巴瘤采取有针对性的生物学方法。

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.