Arsenic stimulates angiogenesis and tumorigenesis in vivo
Arsenic stimulates angiogenesis and tumorigenesis in vivo
复制标题
DOI：
10.1093/toxsci/kfg231
复制
发表时间：
2003-12-01
影响因子：
3.8
通讯作者：
Barchowsky, A
中科院分区：
文献类型：
--
作者：
Soucy, NV;Ihnat, MA;Barchowsky, A
三价无机砷（亚砷酸盐，三氧化二砷，As（III））目前被用于治疗血液肿瘤，并正在研究治疗实体瘤。然而，低浓度的As（III）刺激细胞培养中的血管细胞增殖，尽管这尚未在体内得到证实。因此，在两个体内血管生成模型和一个肿瘤生长模型中测试了As（III）增强血管生长（血管生成）和肿瘤发生的假设。在第一，亚砷酸盐引起的鸡绒毛尿囊膜（CAM）测定血管密度的剂量依赖性增加。阈值As（III）的浓度为0.033 μ M，在浓度大于1 μ M时观察到血管生长的抑制。小鼠基质胶植入物被用来测试血管生成的影响，作为（III）在成年哺乳动物系统。小鼠注射0.8-80 μ g/kg As（III）/天，为期三周。在最后两周期间，将基质胶塞放置在腹壁上。低剂量和高剂量的As（III）与成纤维细胞生长因子-2（FGF-2）在基质胶测定中增加血管密度方面具有协同作用，而中等剂量则没有影响。为了测试As（III）对肿瘤生长的影响，将GFP标记的B16-F10小鼠黑素瘤细胞植入裸鼠中，随后每两周注射0.5-5.0 mg/kg As（III）。在所有动物中均观察到显著的肿瘤生长和肺转移，其中最大的肿瘤发生在用较低剂量的As（III）治疗的动物中。这些研究支持这一假设，并表明诱导血管生成，增强肿瘤生长和转移是砷治疗的潜在剂量依赖性毒副作用。
Trivalent inorganic arsenic (arsenite, arsenic trioxide, As(III) is currently being used to treat hematologic tumors and is being investigated for treating solid tumors. However, low concentrations of As(III) stimulate vascular cell proliferation in cell culture, although this has not been confirmed in vivo. Therefore, the hypothesis that As(III) enhances blood vessel growth (angiogenesis) and tumorigenesis was tested in two in vivo models of angiogenesis and a model of tumor growth. In the first, arsenite caused a dose-dependent increase in vessel density in a chicken chorioallantoic-membrane (CAM) assay. The threshold As(III) concentration for this response was 0.033 muM and inhibition of vessel growth was observed at concentrations greater than 1 muM. Mouse Matrigel implants were used to test the angiogenic effects of As(III) in an adult mammalian system. Mice were injected with 0.8-80 mug/kg As(III)/day over a three-week period. During the last two weeks, Matrigel plugs were placed on the abdominal wall. Low and high doses of As(III) were synergistic with fibroblast growth factor-2 (FGF-2) in increasing vessel density in the Matrigel assay, while a middle dose had no effect. To test the effects of As(III) on tumor growth, GFP-labeled B16-F10 mouse melanoma cells were implanted in nude mice, which subsequently received biweekly injections of 0.5-5.0 mg/kg As(III). Significant tumor growth and lung metastasis was seen in all animals, with the largest tumors occurring in animals treated with lower doses of As(III). These studies support the hypothesis and indicate that induction of angiogenesis, enhanced tumor growth, and metastasis are potential dose-dependent toxic side effects of arsenic therapies.