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Myelotoxicity is a major complication following the delivery of cytotoxic therapy to treat AIDS-associated malignancies in resource-poor countries. Alternative approaches to the management of Burkitts lymphoma and other AIDS-associated non-Hodgkins lymphomas are needed in developing countries where there are limited resources to treat the complications associated with cytotoxic therapy. One possible approach is the use of so-called metronomic therapy. In this approach, cytotoxic drugs are given more frequently but at reduced dosages. To test the feasibility of this approach for treatment of AIDS-Burkitts lymphoma (BL), we first developed a preclinical model. We used the BL-7 cell line to engraft into NOD/SCID mice. The BL-7 cell line is derived from a biopsy from an AIDS-patient with BL, is EBV-positive, has the characteristic c-myc translocation, and has limited passage ex vivo. To determine whether metronomic dosing of cyclophosphamide (CTX) would be effective in the treatment of AIDS-BL, we engrafted NOD/SCID mice with the BL-7 cell line. Four groups of mice were analyzed: BL-7 engrafted SCID mice were given saline i.p. every 6 days (control), CTX at 170 mg/kg i.p. every 6 days for 7 treatments (metronomic i.p.), or CTX at 150 mg/kg i.p. 3 times per week followed by 2 weeks rest and repeated 3 times (maximum tolerated dose). The average time before mice were sacrificed due to tumor growth in the control mice was 56.8 days. When the last control mouse succumbed to tumor growth (65 days), we stopped the treatment of the remaining mice. Mice treated with the maximum tolerated dose of CTX survived until 204 days when the experiment was terminated. No evidence of tumor growth was evident in any of the mice based on necropsy. Sixty percent of mice treated with the metronomic dose of CTX i.p. survived until 204 days without evidence of tumors. The remaining mice did not develop tumors until 193 and 194 days post-engraftment, approximately 137 days following the death of the control mice and cessation of treatment. Weight loss in mice receiving metronomic doses was minimal compared to the mice that had received CTX at maximum tolerated doses. This data indicates that metronomic scheduling of CTX given i.p. significantly enhanced the survival of BL-SCID mice compared to controls and was comparable to CTX given at the maximum tolerated dose. Collectively, these data demonstrate that primary BL cell lines derived from AIDS patients can be successfully engrafted into NOD/SCID mice and are suitable as a preclinical model to test new therapeutic approaches that will limit myelotoxicity.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA