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. ? ? ?
