o-(chloroacetylcarbamoyl)fumagillol and Hyperplasia

To investigate the antitumor apoptotic effect of AGM-1470 by comparing it to that induced by methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) therapy, currently the standard chemotherapy for bladder cancer, in a rat bladder cancer model.. A total of 45 six-week-old female rats were divided into 3 equal groups: those receiving AGM-1470 treatment; those receiving MVAC treatment, and controls. All rats were cystectomized to evaluate the therapeutic effect with regard to macroscopic tumor findings, hematoxylin and eosin pathology, apoptosis detection, and immunohistochemistry (IHC) for bcl-2.. Our experimental protocol succeeded in producing invasive bladder tumors in the majority of rats. Tumor volume was significantly reduced in the AGM-1470 and MVAC treatment groups compared with that in the control group. The apoptotic indices of tumor cells was significantly higher in the AGM-1470 and MVAC treatment groups than in the control group. IHC for bcl-2 demonstrated no statistical difference in expression among the groups. However, the apoptotic indices of high-level bcl-2 expression were significantly lower than the indices of low-level expression in the AGM-1470 group.. AGM-1470 and MVAC appear to exert a prominent mass reduction effect via tumor cell apoptosis in cases of invasive bladder tumor, although these therapies did not demonstrate any obvious modulation of bcl-2 protein expression status. Bcl-2 overexpression might be an obstacle to AGM-1470 therapy because of its significant inhibitory effect on apoptosis.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Cisplatin; Cyclohexanes; Doxorubicin; Female; Gene Expression; Genes, bcl-2; Hyperplasia; Methotrexate; Models, Animal; O-(Chloroacetylcarbamoyl)fumagillol; Papilloma; Rats; Rats, Wistar; Sesquiterpenes; Treatment Outcome; Urinary Bladder; Urinary Bladder Neoplasms; Vinblastine

Anastomotic intimal hyperplasia (AIH) remains an unsolved problem. Angiogenesis around the anastomosis is one of the important mechanisms accelerating AIH. In this study, we investigated the effects of an antiangiogenic agent AGM-1470 (O-[chloroacetyl-carbamoyl] fumagillol: AGM) on the thickness of AIH after expanded polytetrafluoroethylene grafting.. Study 1: Smooth muscle cells (SMCs) were cultured to form 3-mm-side square colonies by using 4 kinds of culture medium, containing AGM at concentrations of 0, 0.1, 1.0, and 10 ng/mL. The SMC colony spreading distance in each group was measured as an index of mitogenic activity. The isolated proliferative activity of SMCs was also assessed. Study 2: Male New Zealand white rabbits underwent inlay expanded polytetrafluoroethylene grafting of the carotid arteries. They were divided in 4 groups (control, vehicle, AGM [0.5], and AGM [5]) in which no topical application, Vaseline ointment, Vaseline ointment containing 0.5 mg AGM, or Vaseline ointment containing 5 mg AGM was applied to the anastomoses, respectively. Rabbits were fed a high-cholesterol diet for 2 weeks before and 8 weeks after the operation. AIH thickness was measured and capillary formation and SMC accumulation around the anastomoses were examined with immunohistochemical staining.. Study 1: AGM suppressed SMC migratory activity in a cytostatic, but not cytotoxic, manner. Study 2: AGM ointment inhibited AIH in proportion to its concentration and also suppressed new capillary formation around the anastomoses and SMC accumulation in AIH.. Topical application of the antiangiogenic agent AGM may become an important strategy for preventing AIH.

Topics: Angiogenesis Inhibitors; Animals; Blood Vessel Prosthesis; Carotid Arteries; Cell Division; Cell Movement; Cells, Cultured; Coloring Agents; Cyclohexanes; Hypercholesterolemia; Hyperplasia; Male; Models, Animal; O-(Chloroacetylcarbamoyl)fumagillol; Ointments; Polytetrafluoroethylene; Postoperative Complications; Rabbits; Sesquiterpenes; Tunica Intima; Vascular Patency

Tumor metastasis can be prevented by inhibiting angiogenesis. In the present study, we have demonstrated that the angiogenesis inhibitor TNP-470 also suppresses the development of primary hepatic nodules. Hepatocarcinogenesis was performed by the feeding of 2-acetylaminofluorene to hepatectomized rats during 8-14 weeks of age. Predominantly arterial-to-portal circulation and sinusoidal capillarization were determined by the staining of nodules with arterially infused ink and immunostaining for factor VIII-related antigen, respectively. Intraperitoneal administration of 30 mg/kg b.w. of TNP-470 twice a week significantly reduced the number of hepatic nodules. Among the nodules, hyperplastic nodules stained with ink, atypical hyperplastic nodules and hepatocellular carcinoma, all of which possess structurally altered sinusoidal endothelial cells or capillary-type endothelial cells, were dramatically decreased in number. Suppression was observed equally in nodules of all sizes. TNP-470 was more effective when administered during 8-20 weeks than during 14-26 weeks. In contrast, ink-non-stained hyperplastic nodules, which have normal sinusoidal endothelial cells, were not affected at all. The present results indicate that TNP-470 suppresses the development of primary hepatic nodules whose microvessels are capillaries or transitional forms from sinusoids to capillaries.

Topics: 2-Acetylaminofluorene; Animals; Antibiotics, Antineoplastic; Carcinogens; Cyclohexanes; Hyperplasia; Liver; Liver Neoplasms, Experimental; Male; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Rats; Rats, Inbred F344; Sesquiterpenes

Using the rat tumour cell line LY80, a subline of Yoshida sarcoma, the effects of AGM-1470 on the growth of primary tumour and the incidence of regional lymph node metastasis were evaluated. AGM-1470 (30 mg kg(-1)) was administered subcutaneously or intravenously. Subcutaneous (s.c.) and intravenous (i.v.) injections were repeated for 8 days and 7 days respectively. Tumour growth of a primary region tended to be suppressed by AGM-1470. The s.c. tumours after sacrifice were much smaller in the AGM-1470-treated group (s.c. injection) than in the control groups. However, the growth of metastatic foci in the lymph nodes was prompted markedly by AGM-1470. All six of the AGM-1470-treated rats had developed swollen axillary lymph nodes and/or brachial lymph nodes on day 19 after tumour implantation (the 7th day after the last treatment) compared with one of six saline-injected rats and three of six vehicle-alone treated rats with swollen axillary lymph nodes. The weight of lymph nodes after sacrifice in the AGM-1470-treated rats was much heavier than that of the other two groups. Histological examination showed that in the AGM-1470-treated group, the cortex and the medulla of the axillary lymph nodes were almost entirely replaced by tumour cells while, in the vehicle alone group, a notable hyperplasia of the lymph nodes due to BT cell proliferation tended to be induced. In the saline group, although a slight hyperplasia of lymph nodes was observed, there were only a few lymph node metastases. In the case of i.v. injection of AGM-1470, similar results were obtained. It is thought that LY80 cells spread to regional lymph nodes at a comparatively early stage by some change or other in which AGM-1470 participated. From the present experiment, it is concluded that application of AGM-1470 alone to patients should be carried out with great caution.

Topics: Animals; Antibiotics, Antineoplastic; Arm; Axilla; Body Weight; Cyclohexanes; Data Interpretation, Statistical; Humans; Hyperplasia; Injections, Intravenous; Injections, Subcutaneous; Lymph Nodes; Lymphatic Metastasis; Male; O-(Chloroacetylcarbamoyl)fumagillol; Rats; Sarcoma, Yoshida; Sesquiterpenes; Time Factors; Tumor Cells, Cultured