ANTI VIRAL THERAPEUTIC FOR EBV MALIGNANCIES

EBV 恶性肿瘤的抗病毒治疗

• 批准号: 6497987
• 负责人: Douglas V Faller
• 金额: $ 40.75万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-07 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6497987
• 关键词: AIDS related neoplasm /cancer; Burkitt's lymphoma; Epstein Barr virus; Hodgkin's disease; arginine; artificial immunosuppression; butyrates; clinical research; clinical trial phase I; combination chemotherapy; drug screening /evaluation; enzyme induction /repression; ganciclovir; human subject; human therapy evaluation; nasopharyngeal neoplasms; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nonHodgkin's lymphoma; thymidine kinase; transcription factor; virus genetics; virus replication

Epstein-Barr Virus is a common and worldwide pathogen. While exposure usually results in a self-limited lymphoproliferative syndrome, infectious mononucleosis, the virus is causative, or associated with, a number of malignancies. The latent virus is detected in 2 endemic tumors: 95% of African Burkitt's lymphoma, and 90-100% of nasopharyngeal carcinoma. Many B-lymphomas, some T-lymphomas, and approximately 50% of Hodgkin's lymphomas have also been found to contain latent EBV. 40% of lymphomas arising in AIDS, and nearly all lymphomas arising in transplant recipients (post-transplant-associated lymphoproliferative disease (PT-LPD) harbor EBV. PT-LPD is especially difficult to treat unless the immunosuppression can be reversed, and is typically refractory to radiation therapy and chemotherapy. Similar to herpes simplex virus and varicella-zoster virus, EBV encodes a thymidine kinase (TK) enzyme. In a rate-limiting step, the viral TK converts nucleoside analogues to their monophosphate form, eventually leading to premature termination of the nascent DNA and cell death. Latently-EBV-infected B-cells and epithelial cells, including tumor cells, do not express TK. We have found that exposure of these cells to the experimental drug Arginine Butyrate results in induction of TK expression. Preliminary in vitro studies demonstrated that induction of EBV-TK in patient-derived tumor cells by Arginine Butyrate is possible, and that these previously-resistant cells are rendered susceptible to Ganciclovir (GCV) therapy. We have years of clinical experience in the administration of Arginine Butyrate to adults and children in studies to induce fetal hemoglobin as therapy for sickle cell anemia and thalassemia. We hypothesized that treatment of patients with EBV- associated tumors with arginine butyrate (to induce the EBV-TK) and GCV (to eliminate EBV-TK expressing cells) might be an effective, nontoxic therapy. We have treated eight patients with Arginine Butyrate plus ganciclovir in an FDA-registered pilot study with documented responses in the majority of patients, and no adverse outcomes related to this regimen. Our Specific Aims are: (1) To determine if treatment with Arginine Butyrate plus Ganciclovir will result in clinical responses in a significant proportion of patients with EBV-associated lymphomas and lymphoproliferative disease (LPD); (2) To determine toxicity or side effects of the combination therapy; and (3) To determine if tumor specimens and cell lines derived from patients demonstrate the same response to Arginine Butyrate and Ganciclovir (with respect to TK gene induction and synergistic susceptibility) as the EBV(+) cell lines we have studied to date.

爱泼斯坦 - 巴尔病毒是一种常见的全球病原体。尽管暴露通常会导致自限性淋巴增生性综合征，感染性单核细胞增多症，但该病毒是致病性或与许多恶性肿瘤有关的。在2种特有肿瘤中检测到潜在病毒：非洲伯基特淋巴瘤的95％，鼻咽癌的90-100％。也发现许多B淋巴瘤，一些T淋巴瘤和大约50％的霍奇金淋巴瘤包含潜在的EBV。 40％在艾滋病中引起的淋巴瘤，几乎所有淋巴瘤在移植受者（移植后相关后相关的淋巴增生性疾病（PT-LPD）港口EBV。PT-LPD均尤其难以治疗，除非可以逆转，并且可以逆转放射治疗，否则PT-LPD尤其难以治疗。静脉曲张病毒，EBV编码胸苷激酶（TK）酶，在限制的步骤中，病毒型TK将核苷类似物转化为单磷酸盐的形式实验性药精氨酸的细胞会导致TK表达诱导。在研究精氨酸的成年人和儿童的研究中，我们有多年的临床经验，以诱导胎儿血红蛋白作为镰状细胞贫血和丘脑贫血的治疗。我们假设治疗EBV相关肿瘤与精氨酸丁酸酯（诱导EBV-TK）和GCV（消除EBV-TK表达细胞）的治疗可能是一种有效的无毒疗法。在FDA注册的试点研究中，我们已经治疗了八名精氨酸丁酸酯和Ganciclovir患者，其中大多数患者的反应记录了，并且与该方案无关。我们的具体目的是：（1）确定用精氨酸丁酸酯加Ganciclovir治疗是否会导致相当比例的EBV相关淋巴瘤和淋巴结增生性疾病（LPD）的大部分患者的临床反应； （2）确定联合疗法的毒性或副作用； （3）确定从患者中得出的肿瘤标本和细胞系是否表现出对精氨酸丁酸酯和ganciclovir的反应（就TK基因诱导和协同敏感性而言）与迄​​今为止研究的EBV（+）细胞系相同。

项目成果

Epstein--Barr virus post-transplant lymphoproliferative disease and virus-specific therapy: pharmacological re-activation of viral target genes with arginine butyrate.

• DOI: 10.1034/j.1399-3062.2001.003003177.x
• 发表时间: 2001-09-01
• 期刊: Transplant infectious disease : an official journal of the Transplantation Society
• 作者: Mentzer, S J;Perrine, S P;Faller, D V
• 通讯作者: Faller, D V