Arsenic trioxide induces dose- and time-dependent apoptosis of endothelium and may exert an antileukemic effect via inhibition of angiogenesis.
Roboz GJ, Dias S, Lam G, Lane WJ, Soignet SL, Warrell RP Jr, Rafii S.
Division of Hematology and Oncology, Weill Medical College of Cornell University, New York, NY 10021, USA.
Arsenic trioxide (As(2)O(3)) has recently been used succe fully in the treatment of acute promyelocytic leukemia and has been shown to induce partial differentiation and apoptosis of leukemic cells in vitro. However, the mechanism by which As(2)O(3) exerts its antileukemic effect remai uncertain. Emerging data suggest that the endothelium and angiogenesis play a seminal role in the proliferation of liquid tumors, such as leukemia. We have shown that activated endothelial cells release cytokines that may stimulate leukemic cell growth. Leukemic cells, in turn, can release endothelial growth factors, such as vascular endothelial growth factor (VEGF). On the basis of these o ervatio , we hypothesized that As(2)O(3) may interrupt a reciprocal loop between leukemic cells and the endothelium by direct action on both cell types. We have shown that treatment of proliferating layers of human umbilical vein endothelial cells (HUVECs) with a variety of concentratio of As(2)O(3) results in a reproducible dose- and time-dependent sequence of events marked by change to an activated morphology, up-regulation of endothelial cell adhesion markers, and apoptosis. Also, treatment with As(2)O(3) caused inhibition of VEGF production in the leukemic cell line HEL. Finally, incubation of HUVECs with As(2)O(3) prevented capillary tubule and branch formation in an in vitro endothelial cell-differentiation a ay. In conclusion, we believe that As(2)O(3 )interrupts a reciprocal stimulatory loop between leukemic cells and endothelial cells by causing apoptosis of both cell types and by inhibiting leukemic cell VEGF production. (Blood. 2000;96:1525-1530)
Cancer Res 1999 Dec 15;59(24):6033-7
Arsenic trioxide causes selective necrosis in solid murine tumors by vascular shutdown.
Lew YS, Brown SL, Griffin RJ, Song CW, Kim JH.
Department of Radiation Oncology, Henry Ford Health System, Detroit, Michigan 48202, USA. younglew@yahoo.com
To investigate the antitumor action of arsenic trioxide in solid tumors, we carried out quantitative tumor perfusion studies, using locally advanced methylcholanthrene-induced fibrosarcoma grown in BALB/c mice. The tumor perfusion studies were a e ed by two separate methods: 99mTc clearance and 86Rb uptake. A single administration of arsenic trioxide (10 mg/kg i.p.) produced a preferential vascular shutdown in the tumor ti ue at 2 and 6 h, leading to ma ive necrosis in the central part of the tumor. The phenomenon was repeatable at intervals of weekly administration of the drug in the same tumor. Normal skin, muscle, and kidney were relativ