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

本研究旨在探讨血管生成抑制剂TNP-470单独及与化疗药物联合应用对大鼠脑肿瘤的抗肿瘤作用。三重标记蓄积研究（^<14>C-TdR、^3 H-FDG、^<99m>Tc-DTPA）已穿孔。在不同孵育时间（10-60 min）后，对细胞和培养基进行称重并测定放射性。示踪剂的摄取值（使用13 Tc-DTPA针对细胞外液和受损细胞进行校正<99m>）被定量为校正的细胞与培养基浓度比。计算^<14>C-TdR和^3 H-FDG的Ki值。培养<14>液中VEGF浓度为0.5 ~ 25 ng/ml时，大鼠脑内皮细胞的增殖（Ki for ^ C-TdR）和葡萄糖代谢（Ki for ^3 H-FDG）呈剂量依赖性增加。在<14>不同浓度的TNP 470（10 ng/ml - 5 μ g/ml）作用下，脑内皮细胞的^ C-TdR和^3 H-FDG的Ki值均降低， ...更多信息 细胞而对C6胶质瘤细胞的抑制作用仅在最高浓度时才能观察到。在体内脑肿瘤模型中，TNP 470的治疗作用也得到了证实。TNP 470（30 mg/kg）皮下给药。在Sprague-Dawley大鼠颅内植入大鼠C6胶质瘤细胞后第6、8、10天。在肿瘤植入后第11天，使用（β <14>C-甲基）-L-甲硫氨酸（Met）获得自传体图像。在TNP 470处理之前或之后，在用和不用30 mg/kg的细胞毒性药物（ACNU）静脉注射处理的大鼠中测量示踪剂摄取，表示为肿瘤/非肿瘤（T/NT），以及对照（既不用TNP 470也不用ACNU处理）。在TNP 470处理的大鼠中，与对照相比，肿瘤体积和Met摄取分别显著减少47%和68%。在使用血管生成抑制剂TNP 470和ACNU的联合方案中，在ACNU治疗后给予TNP 470的大鼠中肿瘤体积和Met摄取均最低。TNP 470处理后ACNU的抑制作用与TNP 470单独处理的抑制作用几乎相同。血管生成抑制剂TNP 470联合细胞毒药物治疗是一种很有前途的脑肿瘤休眠治疗方案。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