Design, Synthesis, and Testing of Breast Cancer Angiogenesis Inhibitors
Annual rept. 15 Jul 1999-14 Jul 2000
MONTEFIORE HOSPITAL AND MEDICAL CENTER BRONX NY
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Thymidine phosphorylase TP catalyzes the phosphorolysis of thymidine and other pyrimidine 2- deoxyribonucleosides. In addition, TP has been shown to possess angiogenic activity in a number of in vitro and in vivo assays, and its angiogenic activity has been linked to its catalytic activity. Several 5- and 6-substituted uracil derivatives were synthesized and evaluated for their ability to inhibit TP activity. In the past year we have identified a 6-amino-substituted uracil analog, 6-2- aminoethylamino-5-chlorouracil AEAC to be one of the most active compounds. AEAC was found to be a competitive inhibitor of TP with a Ki of 165 nM. Human recombinant TP induced human umbilical vein endothelial cell HUVEC migration in a modified Boyden chamber assay in vitro, and this action could be abrogated by the AEAC. This was specific for TP, as the inhibitor had no effect on the chemotactic actions of vascular endothelial growth factor VEGF. HUVEC migration was also induced when TP-transfected human breast carcinoma cells were used in a co-culture assay in place of the purified angiogenic factors, and a TP inhibitor nearly completely blocked the tumor cell- mediated migration. These studies suggest that inhibitors of TP may be useful in breast cancers which are dependent upon TP-driven angiogenesis.
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