o-(chloroacetylcarbamoyl)fumagillol and Inflammation

Angiogenesis, the induction of vessel growth is involved in numerous physiological and pathological processes. While the anti-tumor effect of angiogenesis inhibitors has been extensively investigated in malignant tumors, there is very little information on the effect of angiogenesis inhibitors on inflammation induced angiogenesis. In this report, we utilized a murine model of acute chemically induced cystitis to investigate the ability of three different angiogenesis inhibitors, angiostatin, endostatin and TNP-470, to inhibit the angiogenesis stimulated by this injury. We demonstrate herein, that prophylactic application of the angiogenesis inhibitors led to a significant reduction of each of the inflammatory parameters that were measured. We conclude that anti-angiogenic therapy with angiostatin, endostatin and TNP-470 inhibits inflammation associated angiogenesis induced in this model. We also propose that anti-angiogenic agents may serve as a valuable addition to a standard cyclophosphamid chemotherapy regimen to help reduce the chemotherapy-related side effects while potentially adding an anti-tumor effect.

Topics: Angiogenesis Inhibitors; Angiostatins; Animals; Capillary Permeability; Cyclohexanes; Cyclophosphamide; Cystitis; Disease Models, Animal; Drug Evaluation, Preclinical; Endostatins; Inflammation; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes

Inflammatory conditions are associated with tumor development. IL-1beta is a multifunctional and proinflammatory cytokine that affects nearly all types of cells. To investigate the role of IL-1beta in tumor growth in vivo, we transduced the retroviral vector coding human IL-1beta gene into mouse Lewis lung carcinoma (LLC) cells and subsequently inoculated the transformant (LLC/IL-1beta) to syngeneic C57BL/6 mice. Tumors derived from LLC/IL-1beta grew faster (240%, day 18, vs null-vector control LLC/neo; p < 0.01) and showed more abundant vasculature (250%, vs LLC/neo; p < 0.05), whereas LLC/IL-1beta cells, LLC/neo cells, and wild-type LLC cells did not show any significant difference in the growth rate in vitro. As compared with LLC/neo cells, LLC/IL-1beta cells secreted 2-fold the amount of vascular endothelial growth factor and >10-fold the amount of macrophage-inflammatory protein-2 (CXCL2), one of whose main functions is angiogenesis. Although LLC/IL-1beta itself did not secrete hepatocyte growth factor (HGF), the tumor derived from LLC/IL-1beta cells also contained a >4-fold higher concentration of HGF, another angiogenic factor. In situ hybridization of HGF mRNA in LLC/IL-1beta tumor sections demonstrated that stromal fibroblasts and infiltrating cells overexpressed HGF mRNA. Moreover, when cultured in the presence of HGF in vitro, LLC/IL-1beta cells secreted even larger amounts of vascular endothelial growth factor and macrophage-inflammatory protein-2. The antiangiogenic agent TNP-470 and anti-CXCR2 Ab inhibited the tumor growth of LLC/IL-1beta cells in vivo. These results indicated that secreting IL-1beta into the tumor milieu induces several angiogenic factors from tumor and stromal cells and thus promotes tumor growth through hyperneovascularization.

Topics: Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Animals; Antibodies; Carcinoma, Lewis Lung; Cell Communication; Cell Division; Chemokine CXCL2; Chemokines; Cyclohexanes; Endothelial Growth Factors; Gene Transfer Techniques; Hepatocyte Growth Factor; Humans; Immunohistochemistry; Inflammation; Interleukin-1; Lymphokines; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; O-(Chloroacetylcarbamoyl)fumagillol; Receptors, Interleukin-8B; Sesquiterpenes; Species Specificity; Stromal Cells; Tumor Cells, Cultured; Up-Regulation; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Topics: Anti-Inflammatory Agents; Arthritis, Rheumatoid; Cyclohexanes; Cytokines; Disease Models, Animal; Humans; Inflammation; Integrins; Microcirculation; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Synovial Membrane