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4’-thio-β-D-arabinofuranosylcytosine (T-araC) is an analogue of β-D-arabinofuranosylcytosine (ara-C), a nucleoside that is currently used in the treatment of acute myelogenous leukemia. Unlike ara-C, T-araC showed significant efficacy in treatment of numerous solid tumor xenografts in mice, including colon, lung, prostate, pancreatic, renal, and breast tumors. It has been reported that T-araC acts as an inhibitor for DNA replication, which results in the interruption of cell growth. The excellent in vivo activity of T-araC against a variety of human solid tumors suggests that T-araC may also interfere with tumor angiogenesis. However, T-araC has not been studied for its antiangiogenic effect. In order for a tumor to grow beyond a certain size (∼2 mm3), it must develop a network of blood vessels to maintain its supply of nutrients and oxygen and to remove its toxic waste. The tumor angiogenesis is characterized by oncogene-driven tumor expression of proangiogenic growth factors, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2), key factors involved in tumor angiogenesis and metastasis. We have studied T-araC for its antiangiogenesis activity with human umbilical vein endothelial cells (HUVEC). The preliminary data from cell proliferation and MTS cell viability assays with the HUVEC cells have shown that T-araC is a potent antiangiogenic agent with IC50 values in a low micromolar range. T-araC was highly active against endothelial proliferation when the cells were stimulated by VEGF and FGF-2, both of which are overexpressed in most solid tumors. The findings of this study suggest a role of T-araC in antiangiogenesis and a mechanism of drug action by which T-araC inhibits tumor cell proliferation and neoangiogenesis. These results reveal the potential of T-araC for treatment of human solid tumors.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]