Experimental studies of antitumor effects ofangiogenesis inhibitor TNP-470 with a chemotherapeutic agent on a malignant brain tumor.

本研究的目的是观察血管生成抑制剂TNP-470单独及与化疗药物联合应用对大鼠脑肿瘤的抑制作用。穿孔了三标记蓄积研究(^&lt；14&gt；C-TdR，^~3H-FDG，^&lt；99m&gt；Tc-DTPA)。在不同的孵育时间(10-60min)后，称量细胞和培养基并测定其放射性。用~(99)m&GT；~(99)T-DTPA对细胞外液和受损细胞进行校正后的示踪剂摄取值被量化为校正后的细胞-介质浓度比。计算了~(14)&GT；~(14)C-TdR和~(3 H)-FDG的Ki值。大鼠脑内皮细胞的增殖(Ki)和葡萄糖代谢(Ki)均随培养液中VEGF浓度(0.5~25 ng/ml)的增加而增加。在不同浓度的TNP470(10 ng/ml~5μg/ml)作用下，脑内膜…的Ki值均降低。更多的细胞。相反，只有在最高浓度的TNP470才能观察到对C6胶质瘤细胞的增殖抑制作用。在体内脑瘤模型中，TNP470的治疗作用也得到证实。TNP470(30 mg/kg)皮下注射。SD大鼠脑内种植C6胶质瘤细胞后第6、8、10天。移植瘤后第11天，用(^&lt；14&gt；C-甲基)-L-蛋氨酸(Met)进行自传成像。以肿瘤/非肿瘤(T/NT)表示的示踪剂摄取率，在TNP470处理前或TNP470处理后静脉注射30 mg/kg细胞毒药物(ACNU)的大鼠和对照组(既不注射TNP470也不注射ACNU)的大鼠中测量。在TNP470处理的大鼠中，肿瘤体积和Met摄取量分别比对照组显著减少47%和68%。在使用血管生成抑制剂TNP470和ACNU的联合方案中，在ACNU治疗后再给予TNP470的大鼠的肿瘤体积和Met摄取量都是最低的。TNP470对ACNU的抑制作用与单独应用TNP470几乎相同。血管生成抑制剂TNP470结合细胞毒药物治疗脑肿瘤是一种有前途的肿瘤休眠治疗方案。较少

The aim of this study is to investigate antitumor effects of angiogenesis inhibitor TNP-470 alone and in combination with a chemotherapeutic agent on rat brain tumors.Rat brain endotherial cells and rat C6 glioma cells were grown as mono ayers. Triple-label accumulation studies (^<14>C-TdR,^3H-FDG, ^<99m>Tc-DTPA) were perforated. The cells and medium were weighed and assayed for radioactivity after various periods of incubation (10-60 min). Uptake values of tracers, which were corrected for extracellular fluid and damaged cells using ^<99m>Tc-DTPA, were quantified as a corrected cell-to-medium concentration ratio. Ki values of ^<14>C-TdR and ^3H-FDG were calculated. Proliferation (Ki for ^<14>C-TdR) and glucose metabolism (Ki fo ^3H-FDG) of rat brain endothelial cells increased in a dose - dependent manner of VEGF concentration of medium (0.5-25 ng/ml). The Ki values of ^<14>C-TdR and ^3H-FDG were decreased under various conceSration of TNP470 (10 ng/ml - 5 μ g/ml) in brain endotherial … More cells. In contrast, the antiproliferaion effects on C6 glioma cells were only observed at the highest concentration of TNP470.In an in vivo brain-tumor model, the therapeutic effects of TNP470 were also confirmed. TNP470 (30mg/kg) was given s.c. on days 6, 8, 10 following intracranial implantation of rat C6 glioma cells in Sprague-Dawley rats. On the 11th day after tumor implantation, autobiographic images were obtained using (^<14>C-methyl)-L-methionine (Met). The tracer uptake, represented as tumor/non-tumor (T/NT), was measured in rats treated with and without an intravenous injection of 30mg/kg of cytotoxic drug (ACNU) before or after TNP470 treatment, and control (neither TNP470 nor ACNU treatment). In TNP470-treated rats, tumor volume and Met-uptake were significantly reduced by 47% and 68% compared to the control, respectively. In combination regimens using angiogenesis inhibitor TNP470 and ACNU, both the tumor volume and Met uptake were lowest in the rats treated with the administration of TNP470 following ACNU treatment. The inhibitory effects of ACNU following TNP470 treatments were almost the same as those of TNP470 alone. Angiogenesis inhibitor TNP470 treatment following cytotoxic drugs is a promising protocol in tumor dormant therapy of brain tumors. Less