Nonpeptidomimetic farnesyltransferase inhibitor RPR-115135 increases cytotoxicity of 5-fluorouracil: role of p53.
J Pharmacol Exp Ther
; 300(1): 220-6, 2002 Jan.
Article
em En
| MEDLINE
| ID: mdl-11752120
ABSTRACT
A new nonpeptidic farnesyltransferase inhibitor, RPR-115135, in combination with 5-fluorouracil (5-FU) was studied in an isogenic cell line model system consisting of human colon cancer HCT-116 cells. HCT-116 cells were transfected with an empty control pCMV vector and with a dominant-negative mutated p53 transgene (248R/W). We found that, relative to control transfectants, there was a slight tendency for the p53 inactivated cells to be less sensitive to 5-FU after 6 days of continuous treatment. Simultaneous administration of RPR-115135 and 5-FU, at equitoxic concentrations, resulted in an enhancement of 5-FU cytotoxicity, especially in the CMV-2 clone. Growth inhibition could be accounted for on the basis of a specific cell cycle arrest phenotype (G(2)-M arrest in CMV-2 and S arrest in mutated clones), as assayed by flow cytometry. The combination RPR-115135 + 5-FU increases apoptotic events only in the CMV-2 clone.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteína Supressora de Tumor p53
/
Alquil e Aril Transferases
/
Inibidores Enzimáticos
/
Fluoruracila
/
Indóis
/
Antimetabólitos Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
J Pharmacol Exp Ther
Ano de publicação:
2002
Tipo de documento:
Article
País de afiliação:
Estados Unidos