o-(chloroacetylcarbamoyl)fumagillol and Peritonitis

In patients on long-term peritoneal dialysis (PD), angiogenesis and vasculopathy are observed in the peritoneum, and the degree of vascularization correlates with the area of fibrotic tissue, suggesting the involvement of angiogenesis in the progression of peritoneal fibrosis. The aim of the present study was to evaluate the effect of TNP-470, an anti-angiogenic compound, on the development of peritoneal fibrosis induced by chlorhexidine gluconate (CG).. Peritoneal fibrosis was induced by injection of CG into peritoneal cavity of Institute for Cancer Research (ICR) mice. TNP-470 was injected subcutaneously with CG. Mice were sacrificed, and peritoneal tissues were dissected out at days eight and 16 after CG and TNP-470 injection. The expression patterns of CD31 (as a marker of endothelial cells), vascular endothelial cell growth factor (VEGF), alpha-smooth muscle actin (as a marker of myofibroblasts), heat shock protein 47 (HSP47), type III collagen, F4/80 (as a marker of mice macrophages), proliferating cell nuclear antigen (PCNA), and cyclin-dependent kinase 2 (Cdk2) were examined by immunohistochemistry.. CG-injected mice showed thickening of the submesothelial zone and increased number of vessels, myofibroblasts, and infiltrating macrophages. The expression levels of VEGF, type III collagen, and HSP47 were increased, and a large number of PCNA-positive cells and Cdk2-expressing cells were observed in the thickened submesothelial area. Treatment with TNP-470 suppressed the submesothelial zone thickening and reduced collagen III expression as well as angiogenesis. TNP-470 also decreased the number of VEGF-expressing cells, myofibroblasts, macrophages, PCNA-positive cells, and Cdk2-expressing cells.. Our results indicate the involvement of angiogenesis in the progression of peritoneal fibrosis, and suggest that TNP-470 may be potentially useful for the prevention of peritoneal fibrosis through inhibition of angiogenesis and suppression of myofibroblast proliferation.

Topics: Actins; Angiogenesis Inhibitors; Animals; Chlorhexidine; Collagen Type III; Cyclohexanes; Disease Models, Animal; Female; Fibroblasts; Fibrosis; Heat-Shock Proteins; HSP47 Heat-Shock Proteins; Mice; Mice, Inbred ICR; O-(Chloroacetylcarbamoyl)fumagillol; Peritoneal Dialysis; Peritoneum; Peritonitis; Platelet Endothelial Cell Adhesion Molecule-1; Proliferating Cell Nuclear Antigen; Serpins; Sesquiterpenes; Vascular Endothelial Growth Factor A

The therapeutic effects of the new anti-angiogenesis factor TNP-470 were examined against carcinomatous peritonitis in mice. In the first experiment using carcinomatous peritonitis caused by i.p. inoculation of 10(6) M5076 tumor cells, TNP-470 solution was injected i.p. in a bolus of 50 mg/kg body weight into two groups of 10 mice either 1 or 8 days after the i.p. inoculation. The administration of TNP-470 on day 1 extended the survival time of the mice compared with 10 control mice receiving no treatment, whereas TNP-470 given on day 8 did not affect the survival time. In the next experiment on the M5076 tumor, TNP-470 solutions at 100 or 300 mg/kg were injected i.p. in a bolus into two groups of 20 mice 1 day after the inoculation 10(6) tumor cells, respectively. The administration of TNP-470 at 100 mg/kg also had an inhibitory effect. However, TNP-470 at 300 mg/kg caused toxic death in half of the mice. Next, we examined the effects of TNP-470 on another type of carcinomatous peritonitis model, which was caused by i.p. inoculation of 10(6) B16 melanoma cells. In this experiment, TNP-470 solutions in a bolus of 150 mg/kg were injected i.p. into six groups of 10 mice each on day 1 only (group 1), on days 1 and 4 (group 2), on days 1, 4 and 7 (group 3), on day 8 only (group 4), on days 8 and 11 (group 5), or on days 8, 11 and 14 (group 6), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antibiotics, Antineoplastic; Cyclohexanes; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Peritoneal Neoplasms; Peritonitis; Sesquiterpenes; Tumor Cells, Cultured

In order to perform therapy for carcinomatous peritonitis by a new angiogenesis inhibitor, TNP-470, we investigated the effective timing and the optimal doses for intraperitoneal administration using two mice models. In both carcinomatous peritonitis models caused by M 5076 tumor and B 16 melanoma, the early administration of TNP-470 within one week after tumor inoculation extended the survival times of the mice receiving the drugs, whereas the administration of TNP-470 one week or later after inoculation did not affect the survival time. However, there were significant differences in the effective therapeutic doses of TNP-470 between the two models. It is important to select the best timing and doses for intraperitoneal administration of TNP-470 based on the state of angiogenesis and the sensitivity of the tumor tissues to TNP-470.

Topics: Animals; Antibiotics, Antineoplastic; Cyclohexanes; Infusions, Parenteral; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Invasiveness; O-(Chloroacetylcarbamoyl)fumagillol; Peritonitis; Sarcoma, Experimental; Sesquiterpenes

TNP-470, an analog of fumagillin, is one of the new angiogenesis inhibitors. Five days after an intraperitoneal inoculation of 10(7) cells of Walker 256 carcinosarcoma to SD rats, TNP-470 was injected intraperitoneally in the form of TNP aqueous solution or TNP-oil solution. Mean survival time of rats given TNP-oil solution or TNP aqueous solution was statistically prolonged, compared with that of the control rats. Our results showed that TNP-470 is an effective therapeutic drug for carcinomatous peritonitis.

Topics: Animals; Antibiotics, Antineoplastic; Carcinoma 256, Walker; Cyclohexanes; Infusions, Parenteral; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; O-(Chloroacetylcarbamoyl)fumagillol; Peritonitis; Rats; Sesquiterpenes