PT  - JOURNAL ARTICLE
AU  - J C Wurzer
AU  - R J Tallarida
AU  - M A Sirover
TI  - New mechanism of action of the cancer chemotherapeutic agent 5-fluorouracil in human cells.
DP  - 1994 Apr 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 39--43
VI  - 269
IP  - 1
4099  - http://jpet.aspetjournals.org/content/269/1/39.short
4100  - http://jpet.aspetjournals.org/content/269/1/39.full
SO  - J Pharmacol Exp Ther1994 Apr 01; 269
AB  - 5-Fluorouracil (5-FlUra), a cancer chemotherapeutic agent used in the treatment of colon, breast, ovarian and prostate cancer, is incorporated into DNA as a result of its utilization as 5-FldUTP during DNA synthesis. This promutagenic DNA lesion is excised by the base excision repair enzyme uracil DNA glycosylase (UDG). In this report we describe for the first time a mechanism by which 5-FlUra as the free base specifically binds in vivo to the UDG in noncycling human cells, thereby inhibiting its activity. By using 5-FlUra concentrations which did not elicit demonstrable cell toxicity, a dose-dependent decrease in UDG activity was detected which approached 30% of that observed in control cells. In contrast, exposure of cells to equivalent concentrations of uracil, 5-fluorodeoxyuridine or 5-bromouracil had no effect on UDG activity. Subsequent studies demonstrated a reversible binding of 5-FlUra to the glycosylase. Kinetic analysis using nonlinear regression analysis demonstrated a competitive mode of inhibition and indicated a tight binding of 5-FlUra to UDG in vivo, although the 5-FlUra-UDG complex was easily dissociated in vitro. These findings describe a potentially new and novel mechanism of action of 5-FlUra in a nonproliferating human cell population. The potential relevance of these findings to the utility of 5-FlUra as a cancer chemotherapeutic agent is considered.