o-(chloroacetylcarbamoyl)fumagillol and Nasopharyngeal-Neoplasms

This study was conducted to evaluate the effectiveness of angiogenesis inhibitor 6-O-(N-chloroacetyl-carbamoyl)-fumagillol (TNP-470. AGM-1470) in the treatment of nasopharyngeal carcinoma (NPC) alone and in combination with cytotoxic agents. Forty-two male BALB/c nude mice bearing human NPC cell line CNE-2 were randomized into 6 groups: those treated with saline solution, TNP-470, cisplatin (DDP), fluorouracil (5-FU), TNP-470 + DDP, and TNP-470 + 5-FU, respectively. In every treatment group, tumor growth was suppressed significantly. The combination of 5-FU with TNP-470 showed significant enhancement in antitumor efficacy. TNP-470 also enhanced the inhibitory effect of DDP, although not to statistical significance. All animals gained in body weight, although treatment with 5-FU caused slight, reversible diarrhea of 2 to 3 days' duration. The results showed that TNP-470 suppressed the growth of the human NPC cell line and enhanced the antitumor effect of 5-FU without increasing its toxicity. The combination of angiogenesis inhibitors with conventional cytotoxic agents is promising in the treatment of NPC.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Cisplatin; Cyclohexanes; Drug Evaluation, Preclinical; Fluorouracil; Male; Mice; Mice, Inbred BALB C; Nasopharyngeal Neoplasms; Neoplasm Transplantation; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Tumor Cells, Cultured

The efficacy and targeting cells of angiogenesis inhibitor TNP-470 on human squamous cell nasopharyngeal carcinoma (NPC) were investigated. The colorimetric MTT assay was used to evaluate the IC50 values of NPC/HK1 cells and human dermal microvascular endothelial cells (HDMEC) for TNP-470. An NPC human tumor model was built by tumor-bearing nude mice using the NPC cell line of NPC/HK1. TNP-470 (30 mg/kg s.c.) was injected every other day. The results showed that the IC50 of NPC/HK1 cells for TNP-470 was 3.8 times higher than that of HDMEC. A significant difference in tumor volume between control and treatment groups was found after 7 days of treatment and increased thereafter. At the end of the treatment, tumor volume was 773.7 +/- 287.1 mm3 (n = 8) in the control group versus 454.5 +/- 132.8 mm3 (n = 8) in the treatment group (p = 0. 013); the ratio of the mean tumor volume in treated animals to that of control animals was 0.587, resulting a 41.3% decrease in tumor growth. The necrotic area was larger in the treatment group. Physical toxicity did not result from the treatment. These studies suggest that angiogenesis inhibitor TNP-470 is effective in the treatment of squamous cell NPC without obvious toxicity.

Topics: Antibiotics, Antineoplastic; Cyclohexanes; Humans; Nasopharyngeal Neoplasms; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Tumor Cells, Cultured

To evaluate the efficacy of the angiogenesis inhibitor AGM-1470 for the experimental treatment of nasopharyngeal carcinoma (NPC).. A NPC human tumour model was built by tumour-bearing nude mice using the NPC cell line CNE-2. Twenty-one BALB/c nude mice bearing CNE-2 xenografts were randomized into a treatment group and a control group. In the treatment group, AGM-1470 was injected 30 mg/kg subcutaneously every other day; while the vehicle (three per cent ethanol solution in 0.9 per cent saline) was given to the mice in control group. Tumour volumes and animal weights were measured every third day. Autopsy was performed after 18 days of treatment. The tumour tissue as well as the murine tissues of heart, kidney, and liver in each mouse were removed for formalin fixation and routine HE staining. Pathological evaluation was performed in these tissues.. There was a significant difference in tumour volume between the two groups at day 9 of treatment and this increased thereafter. At day 15 of treatment, the tumour volume was 4251 +/- 559 mm3 (n = 10) in the control group versus 3122 +/- 967 mm3 (n = 11) in the AGM-1470 treated group (p = 0.004); and T:C ratio (mean tumour volume of treated/mean tumour volume of control) was 0.73, resulting in a 27 per cent decrease in tumour growth. Central necrosis and consequential shrinkage of tumours occurred in both groups at the end of experiment. Physical toxicity and histological toxicity of heart, liver, and kidney did not result from AGM-1470 therapy.. AGM-1470 suppresses the growth of the human NPC cell line CNE-2. Treatment by AGM-1470 has no physical nor histological toxicity. Angiogenesis inhibitors may be effective in the treatment of the local lesion of NPC.

Topics: Animals; Antibiotics, Antineoplastic; Cyclohexanes; Drug Screening Assays, Antitumor; Male; Mice; Mice, Inbred BALB C; Nasopharyngeal Neoplasms; Neoplasm Transplantation; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Time Factors; Tumor Cells, Cultured