5--deoxy-5-fluorocytidine and Uterine-Cervical-Neoplasms

A series of tumor-activated prodrugs of the inhibitors of dihydropyrimidine dehydrogenase (DPD), an enzyme catabolizing 5-fluorouracil (5-FU: 4g), has been designed and synthesized. RO0094889 (11c) is a prodrug of 5-vinyluracil (4c), a known DPD inhibitor, and was designed to generate 4c selectively in tumor tissues by sequential conversion of 11c by three enzymes: esterase, cytidine deaminase and thymidine phosphorylase, the latter two of which are known to be highly expressed in various tumor tissues. When capecitabine (1), a tumor-activated prodrug of 5-FU, was co-administered orally with 11c, 5-FU in tumor tissues was significantly increased with only a slight increase of 5-FU in plasma as compared with oral capecitabine alone.

Topics: Administration, Oral; Animals; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Carcinoma, Non-Small-Cell Lung; Cytidine Deaminase; Deoxycytidine; Dihydrouracil Dehydrogenase (NADP); Drug Design; Drug Stability; Esterases; Female; Fluorouracil; Humans; Lung Neoplasms; Mice; Oxidoreductases; Prodrugs; Thymidine Phosphorylase; Tissue Distribution; Uracil; Uterine Cervical Neoplasms; Xenograft Model Antitumor Assays