Soucy Nicole V, Ihnat Michael A, Kamat Chandrashekhar D, Hess Linda, Post Mark J, Klei Linda R, Clark Callie, Barchowsky Aaron
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Toxicol Sci. 2003 Dec;76(2):271-9. doi: 10.1093/toxsci/kfg231. Epub 2003 Sep 11.
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 microM and inhibition of vessel growth was observed at concentrations greater than 1 microM. 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 microg/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.
三价无机砷（亚砷酸盐、三氧化二砷、As[III]）目前正用于治疗血液系统肿瘤，并且正在进行治疗实体瘤的研究。然而，低浓度的As(III)在细胞培养中会刺激血管细胞增殖，尽管这一点尚未在体内得到证实。因此，在两种体内血管生成模型和一种肿瘤生长模型中对As(III)促进血管生长（血管生成）和肿瘤发生的假说进行了验证。在第一个模型中，在鸡胚绒毛尿囊膜（CAM）试验中，亚砷酸盐导致血管密度呈剂量依赖性增加。这种反应的As(III)阈值浓度为0.033微摩尔，在浓度大于1微摩尔时观察到血管生长受到抑制。使用小鼠基质胶植入物在成年哺乳动物系统中测试As(III)的血管生成作用。在三周的时间内，给小鼠注射0.8 - 80微克/千克As(III)/天。在最后两周，将基质胶栓置于腹壁上。在基质胶试验中，低剂量和高剂量的As(III)与成纤维细胞生长因子-2（FGF-2）协同增加血管密度，而中等剂量则无作用。为了测试As(III)对肿瘤生长的影响，将绿色荧光蛋白标记的B-16-F10小鼠黑色素瘤细胞植入裸鼠体内，随后每两周给这些裸鼠注射0.5 - 5.0毫克/千克As(III)。在所有动物中均观察到显著的肿瘤生长和肺转移，最大的肿瘤出现在接受较低剂量As(III)治疗的动物中。这些研究支持了这一假说，并表明血管生成的诱导、肿瘤生长的增强和转移是砷疗法潜在的剂量依赖性毒性副作用。
