o-(chloroacetylcarbamoyl)fumagillol and Leukemia

The aim of this study was to evaluate the effects of an angiogenesis inhibitor in a non-immunocompromised setting in which transplanted tumor cells home and expand in a manner mimicking the original tumor in the donor. We used a novel animal model for T-cell lymphoma/leukemia (TLL) to test the antitumor effect of TNP-470, a well-established angiogenesis inhibitor.. Cells from spontaneously arisen TLL tumors were transferred to syngenic recipients. The mice were treated with TNP-470 (30 mg/kg) or vehicle every other day for 2 weeks. Mice were sacrificed on day 15 after transfer, and body and organ weights were measured. Cell cycle and morphologic analysis was performed on cells and/or sections from selected organs. The cytotoxic effect of TNP-470 was assayed in vitro using the TLL-M and HL-60 cell lines.. TNP-470 treatment significantly reduced total tumor load and tumor mass in specific organs infiltrated with lymphoma/leukemia. This was associated with an increased apoptosis in these organs. We also observed side effects of TNP-470 not previously reported, such as diminished extramedullary erythropoiesis and disrupted liver morphology. In vitro TLL-M cells were resistant to cytotoxic effects of moderate doses of TNP-470.. TNP-470 treatment has a beneficial effect on tumor load in the TLL transfer model, most likely caused by the antiangiogenic effect of TNP-470. This is supported by the observation of increased apoptosis in infiltrated organs. The TLL transfer model is well suited for further studies of combinations with TNP-470 or other angiogenesis inhibitors and cytotoxic drugs.

Topics: Angiogenesis Inhibitors; Animals; Antibiotics, Antineoplastic; Apoptosis; Cell Division; Cyclohexanes; Drug Evaluation, Preclinical; Erythropoiesis; Hematopoiesis, Extramedullary; HL-60 Cells; Humans; Leukemia; Leukemic Infiltration; Liver; Lymphoma; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Transplantation, Isogeneic; Treatment Outcome