Antiangiogenic Therapy for AIDS-Associated Lymphomas

描述(由申请人提供)：艾滋病流行的负担在非洲最严重，那里用于治疗艾滋病毒和艾滋病毒相关疾病的资源有限。随着艾滋病在非洲的流行继续增长，与艾滋病相关的恶性肿瘤也在增加，其中包括与艾滋病相关的伯基特淋巴瘤(BL)。目前的治疗模式依赖于以最大耐受量给予细胞毒药物。然而，在资源有限的情况下，接受这些强化联合化疗方案的患者缺乏支持性护理，导致无法接受的高死亡率。在资源贫乏的国家，需要替代方法来治疗淋巴瘤和其他与艾滋病相关的非霍奇金淋巴瘤。一种新的替代方法使用标准的化疗药物，但按照节拍(慢性、持续和低剂量)时间表给药。细胞毒性药物的节律程序被认为是为了抑制肿瘤内内皮细胞的发展，并阻止血管生成。由于药物剂量较低，减少了骨髓抑制和相关毒性。本应用程序的目的是开发一个艾滋病相关性白血病的临床前模型，以测试这一新的治疗方法，并在该模型中测试节律疗法。我们将开发一种慢病毒载体，用荧光素酶转导原代AIDS-BL细胞系，通过生物发光成像来监测肿瘤的生长和治疗反应。将原代AIDS-BL系移植到NOD/SCID小鼠体内，将产生一种更接近人类临床疾病的原位BL模型。利用这个艾滋病的临床前模型，我们将确定通过采用有节律的化疗药物方案来靶向血管生成是否可以诱导缓解和减少毒性。我们的临床假设是，更频繁地给予低剂量的细胞毒药物组合将抑制移植到NOD/SCID小鼠的原代AIDS-BL细胞系中内皮细胞的发展，并导致长期的肿瘤消退。我们的长期目标是开发基于机制的疗法来治疗淋巴瘤和其他与艾滋病相关的非霍奇金淋巴瘤，以满足资源匮乏、支持性护理有限的情况下的独特需求。这项研究的成功完成将使我们能够向前迈进，在临床上测试细胞毒药物的节律剂量。项目简介：这项拟议研究的目标是开发一种临床前模型来测试艾滋病相关淋巴瘤的新化疗方法。

DESCRIPTION (provided by applicant): The burden of the AIDS epidemic is highest in Africa where resources are limited for the treatment of HIV and for HIV-associated diseases. And as the AIDS epidemic continues to grow in Africa, AIDS-related malignancies are also increasing including AIDS-related Burkitt's lymphoma (BL). The current treatment paradigm relies on cytotoxic drugs given at the maximum tolerated dose. However, in the resource-constrained setting, there is a lack of supportive care available to patients undergoing these intensive combination chemotherapy regimens resulting in unacceptably high mortality rates. Alternative approaches to the treatment of BL and other AIDS-related non-Hodgkin's lymphomas are needed in resource-poor countries. A new alternative approach utilizes standard chemotherapeutic drugs but delivers them at a metronomic (chronic, continuous and low-dose) schedule. The metronomic scheduling of cytotoxic drugs is hypothesized to inhibit the development of endothelial cells within the tumor and block angiogenesis. Because of the lower doses of drugs, there is reduced myelosuppression and associated toxicities. The objectives of this application are to develop a preclinical model of AIDS- associated BL to test this new therapeutic approach and to test metronomic therapy in this model. We will develop a lentiviral vector to transduce primary AIDS-BL cell lines with luciferase to monitor tumor growth and response to treatment by bioluminescent imaging. The use of primary AIDS-BL lines engrafted into NOD/SCID mice intraperitoneally will generate an orthotopic model of BL that more closely resembles human clinical disease. Using this preclinical model of AIDS-BL, we will determine whether targeting of angiogenesis by adopting a metronomic schedule of chemotherapeutic drugs can induce remission and reduce toxicity. Our clinical hypothesis is that low-doses of combinations of cytotoxic agents given more frequently will inhibit the development of endothelial cells in primary AIDS-BL cell lines engrafted in NOD/SCID mice and result in long-lasting tumor regression. Our long-term goal is to develop mechanism-based therapies for the treatment of BL and other AIDS-related non-Hodgkin's lymphomas that address the unique needs in resource poor settings where supportive care is limited. The successful completion of this research will allow us to move forward to test metronomic dosing of cytotoxic drugs in the clinic. PROJECT NARRATIVE: The goal of the proposed research is to develop a preclinical model to test new chemotherapies for AIDS-associated lymphomas.