Jc. Wurzer et al., NEW MECHANISM OF ACTION OF THE CANCER CHEMOTHERAPEUTIC AGENT 5-FLUOROURACIL IN HUMAN-CELLS, The Journal of pharmacology and experimental therapeutics, 269(1), 1994, pp. 39-43
5-Fluorouracil (5-FIUra), a cancer chemotherapeutic agent used in the
treatment of colon, breast, ovarian and prostate cancer, is incorporat
ed into DNA as a result of its utilization as 5-FldUTP during DNA synt
hesis. This promutagenic DNA lesion is excised by the base excision re
pair enzyme uracil DNA glycosylase (UDG). In this report we describe f
or the first time a mechanism by which 5-FIUra as the free base specif
ically binds in vivo to the UDG in noncycling human cells, thereby inh
ibiting its activity. By using 5-FIUra concentrations which did not el
icit demonstrable cell toxicity, a dose-dependent decrease in UDG acti
vity was detected which approached 30% of that observed in control cel
ls. In contrast, exposure of cells to equivalent concentrations of ura
cil, 5-fluorodeoxyuridine or 5-bromouracil had no effect on UDG activi
ty. Subsequent studies demonstrated a reversible binding of 5-FIUra to
the glycosylase. Kinetic analysis using nonlinear regression analysis
demonstrated a competitive mode of inhibition and indicated a tight b
inding of 5-FIUra to UDG in vivo, although the 5-FIUra-UDG complex was
easily dissociated in vitro. These findings describe a potentially ne
w and novel mechanism of action of 5-FIUra in a nonproliferating human
cell population. The potential relevance of these findings to the uti
lity of 5-FIUra as a cancer chemotherapeutic agent is considered.