In this pilot study we propose to prepare novel prodrugs based upon 5F- uracil (FU) and to test their effectiveness against human breast normal mammary epithelial and tumor derived breast cells lines in culture. FU is one of the most used anticancer drugs. It has greater activity in combination with leucovorin. We will start with 5-F-orotate (FO), which is metabolically converted to FU nucleotides. Conversion of FO to these end products requires steps of the pyrimidine path way different from those for FU. The required enzymes in combination are reported to be 10x more active in tumor than in normal cells, and on this basis FO should have a good therapeutic index. FO does not readily enter human cells because of its negatively charged carboxylate anion. Esterifying it with acyloxyalkylester derivatives will allow entry into cells, where this group is readily removed and releases FO for rapid conversion to the toxic end products. The same principle is proposed for later testing of other charged potential anti-neoplastic agents.
