Opposing effects of arsenic trioxide on hepatocellular carcinomas in mice.

Arsenic trioxide (As₂O₃) is a potent antitumor agent used to treat acute promyelocytic leukemia (APL) and, more recently, solid tumors. However, the dose of As₂O₃ required to suppress human xenographs in mice is markedly higher than that used to treat APL in humans. Paradoxically, low doses of As₂O₃ stimulate angiogenesis, which might be expected to promote tumor growth. Clearly, appropriate dosages of As₂O₃ are required to treat human patients to avoid toxicity and undesirable side effects. In the present study, we investigated As₂O₃ with respect to its toxicity and effects on tumor growth, angiogenesis and cell apoptosis using H22 hepatocellular carcinoma (HCC) cells in a mouse model of HCC. As₂O₃ inhibited tumor growth and angiogenesis, and enhanced tumor cell apoptosis at doses greater than 1 mg/kg, but mice lost weight and failed to thrive at doses of 4 mg/kg and greater. In contrast, low doses (<1 mg/kg) of As₂O₃ promoted tumor growth, upregulated the expression of vascular endothelial growth factor and tumor angiogenesis, and had no effect on tumor cell apoptosis. In vitro studies demonstrated that As₂O₃ inhibited the proliferation of H22 tumor cells and bovine aortic endothelial cells, and induced their apoptosis in a dose- and time-dependent fashion, suggesting that the mechanism of As₂O₃-mediated inhibition of tumor growth is due to direct effects of the drug on both tumor cells and endothelia. In summary, different doses of As₂O₃ have opposing effects on tumor growth and angiogenesis. The results demonstrate that As₂O₃ has a narrow window of therapeutic opportunity with respect to dosage, and that low doses of the drug as used in metronomic therapy should be used with extreme caution. ( Cancer Sci 2006; 97: 675–681) [ABSTRACT FROM AUTHOR]