Arsenic stimulates angiogenesis and tumorigenesis in vivo

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.