New mechanism of action of the cancer chemotherapeutic agent 5-fluorouracil in human cells.
J Pharmacol Exp Ther
; 269(1): 39-43, 1994 Apr.
Article
en En
| MEDLINE
| ID: mdl-8169845
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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
ADN Glicosilasas
/
Fluorouracilo
/
N-Glicosil Hidrolasas
Límite:
Humans
Idioma:
En
Revista:
J Pharmacol Exp Ther
Año:
1994
Tipo del documento:
Article
Pais de publicación:
Estados Unidos