A. Roy, Rongbao Li, Zhican Qu
Apr 15, 2006
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Influential Citations
3
Citations
Quality indicators
Journal
Cancer Research
Abstract
235 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine (clofarabine) is a new-generation nucleoside analog discovered by Southern Research Institute based on the experience with cladribine and fludarabrine. Clofarabine has demonstrated significant single-agent antitumor activity and has recently been approved by the FDA for the treatment of pediatric patients with relapsed or refractory acute lymphoblast leukemia. Clofarabine has also shown significant efficacy in xenograft models of solid tumors; its activity in solid tumors is presently being investigated clinically. It is known that clofarabine inhibits DNA synthesis and repair and induces apoptosis by disrupting the integrity of mitochondrial membranes. However, it has not been tested if clofarabine is active against tumor angiogenesis that is required for a solid tumor to grow beyond 2 mm in diameter. In this study, we have investigated the effect of clofarabine on endothelial cell proliferation, migration and differentiation into capillary vessels, the key steps in angiogenesis. The results show that clofarabine inhibits human endothelial cell proliferation, with an IC50 value in sub-micromolar range, and also their migration towards the angiogenic factors, an important functional property of endothelial cells to form the vascular network. Clofarabine, also, clearly interrupts the endothelial cell differentiation to form endothelial tubes. These results indicate that clofarabine is not only active against tumor cell growth, but also active against endothelial cells to inhibit its proliferation, migration and microvessel tube formation, suggesting an important role of clofarabine in antiangiogenesis. Further studies on the mechanism by which clofarabine inhibits neoangiogenesis are being undertaken. These findings highlight the potential of clofarabine as an effective agent against human solid tumors, which combines anti-proliferative and antiangiogenic activities in one molecule, and provide information to further optimize dosage and sequence of clofarabine treatment in future clinical trials.