o-(chloroacetylcarbamoyl)fumagillol and Lymphoma

Anti-apoptotic proteins that block death receptor-mediated apoptosis favour tumour evasion of the immune system, leading to enhanced tumour progression. However, it is unclear whether blocking the mitochondrial pathway of apoptosis will protect tumours from immune cell attack. Here, we report that the anti-apoptotic protein Bcl-xL , known for its ability to block the mitochondrial pathway of apoptosis, exerted tumour-progressive activity in a murine lymphoma model. Bcl-xL overexpressing tumours exhibited a more aggressive development than control tumours. Surprisingly, Bcl-xL protection of tumours from NK cell-mediated attack did not involve protection from NK cell-mediated cytotoxicity. Instead, Bcl-xL -blocked apoptosis resulting from hypoxia and/or nutrient loss associated with the inhibition of angiogenesis caused by NK cell-secreted IFN-γ. These results support the notion that NK cells may inhibit tumour growth also by mechanisms other than direct cytotoxicity. Hence, the present results unravel a pathway by which tumours with a block in the mitochondrial pathway of apoptosis can evade the immune system.

Topics: Animals; bcl-X Protein; Cell Line, Tumor; Cyclohexanes; Cytotoxicity, Immunologic; Humans; Interferon-gamma; Killer Cells, Natural; Lymphoma; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Tumor Escape

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

Topics: Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Cells; Cells, Cultured; Colony-Forming Units Assay; Cyclohexanes; Cyclophosphamide; Dose-Response Relationship, Drug; Doxorubicin; Hematopoietic Stem Cells; Humans; Lymphoma; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Prednisolone; Sesquiterpenes; Vincristine