Antiangiogenic Therapy for AIDS-Associated Lymphomas

说明（由申请人提供）：艾滋病流行病的负担在非洲最为沉重，因为用于治疗艾滋病毒和与艾滋病毒有关的疾病的资源有限。随着艾滋病在非洲的蔓延，与艾滋病有关的恶性肿瘤也在增加，包括与艾滋病有关的伯基特淋巴瘤（BL）。目前的治疗模式依赖于以最大耐受剂量给予细胞毒性药物。然而，在资源有限的情况下，对接受这些强化联合化疗方案的患者缺乏可用的支持性护理，导致不可接受的高死亡率。在资源贫乏的国家，需要治疗BL和其他与艾滋病相关的非霍奇金淋巴瘤的替代方法。一种新的替代方法是利用标准的化疗药物，但以有节奏的（慢性、连续和低剂量）时间表给药。假设细胞毒性药物的节律性调度抑制肿瘤内内皮细胞的发育并阻断血管生成。由于药物剂量较低，骨髓抑制和相关毒性减少。本申请的目的是开发艾滋病相关BL的临床前模型，以测试这种新的治疗方法，并在该模型中测试节拍疗法。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，通过生物发光成像监测肿瘤生长和对治疗的反应。将原代AIDS-BL细胞系腹腔移植到NOD/SCID小鼠体内，将产生更接近人类临床疾病的原位BL模型。利用这个AIDS-BL的临床前模型，我们将确定采用节律性化疗药物的靶向血管生成是否可以诱导缓解和降低毒性。我们的临床假设是，在NOD/SCID小鼠移植的原发AIDS-BL细胞系中，频繁使用低剂量的细胞毒性药物组合会抑制内皮细胞的发育，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治疗方法，用于治疗BL和其他艾滋病相关的非霍奇金淋巴瘤，以解决资源贫乏环境中支持治疗有限的独特需求。这项研究的成功完成将使我们能够在临床测试细胞毒性药物的节律剂量。项目描述：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.