Design, Synthesis, and Testing of Breast Cancer Angiogenesis Inhibitors
Abstract
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-aminoethyl)amino-5-chlorouracil (AEAC) to be one of the most active compounds. AEAC was found to be a competitive inhibitor of TP with a K(sub i) 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2002
- Accession Number
- ADA405320
Entities
People
- Edward L. Schwartz