Suppression of P-glycoprotein expression and multidrug resistance by DNA cross-linking agents.
Clin Cancer Res
; 3(8): 1339-46, 1997 Aug.
Article
en En
| MEDLINE
| ID: mdl-9815817
Overexpression of the trans-membrane drug efflux pump P-glycoprotein is one of the major mechanisms by which cancer cells develop multidrug resistance. We demonstrated previously that noncytotoxic doses of various genotoxic chemicals, particularly DNA cross-linking agents, preferentially altered expression of inducible genes. These effects occurred principally at the transcriptional level and were closely correlated temporally with DNA damage. Because the mdr1 gene coding for P-glycoprotein has been reported to be highly inducible, we were interested in the effects of genotoxic cancer chemotherapy agents on its expression. We report that the DNA cross-linking agent mitomycin C significantly suppressed mRNA and protein expression of P-glycoprotein and decreased the rate of drug efflux. Mitomycin C pretreatment also significantly increased the sensitivity of cancer cells to subsequent killing by the P-glycoprotein substrate doxorubicin, decreasing the ED50 by 5- to 10-fold. Suppression of P-glycoprotein expression was also observed with subtoxic doses of the DNA cross-linking agents cisplatin, BMS181174, and chromium(VI). These effects occurred in both human and rodent cell lines; in cell lines derived from colon, breast, leukemia, neuroblastoma, and hepatoma tumors; and under both monolayer and "spheroid" culture conditions. These results suggest the basis for novel clinical cancer chemotherapy regimens aimed at drug-resistant tumors, in which a sub-chemotherapeutic dose of a DNA cross-linking agent is used to modulate the multidrug resistance phenotype prior to treatment with a second cytotoxic agent.
Buscar en Google
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Transcripción Genética
/
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP
/
Resistencia a Múltiples Medicamentos
/
Reactivos de Enlaces Cruzados
/
Mitomicinas
/
Antineoplásicos
Límite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Clin Cancer Res
Asunto de la revista:
NEOPLASIAS
Año:
1997
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos