Idarubicin DNA intercalation is reduced by MRP1 and not Pgp.
Leukemia
; 13(9): 1390-8, 1999 Sep.
Article
em En
| MEDLINE
| ID: mdl-10482990
ABSTRACT
Currently available data regarding the substrate specificity of the multi-drug resistance (MDR) mechanisms P-glycoprotein (Pgp) and MDR-associated protein (MRP1) for idarubicin are inconclusive. A multiparameter flow cytometry method was developed which allows simultaneous quantitative measurement of total cellular fluorescence and the amount of anthracyclines intercalated into the DNA. Anthracycline DNA intercalation was measured by fluorescence resonance energy transfer (FRET) between Hoechst 33342 and anthracyclines. Daunorubicin and idarubicin accumulation were studied and compared in established cell lines expressing Pgp and MRP1. The data demonstrate that daunorubicin DNA intercalation is affected by both Pgp and MRP1 whereas idarubicin DNA intercalation is affected only by MRP1. MRP1 and Pgp function could be blocked completely by 5 microM PAK 104P, while higher concentrations of verapamil, PSC 833 and cyclosporin A were necessary to attain complete blocking of MRP1 compared to Pgp. Daunorubicin DNA intercalation correlates better with cell survival and is more sensitive at physiological MDR expression as observed in hematopoietic progenitors than daunorubicin levels measured by total cellular fluorescence. In conclusion, idarubicin DNA intercalation is reduced by MRP1 but not by Pgp. PAK-104P is an effective modulator for both Pgp and MRP1 and may further improve idarubicin efficacy.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Idarubicina
/
Membro 1 da Subfamília B de Cassetes de Ligação de ATP
/
Pareamento Incorreto de Bases
/
Proteínas Associadas à Resistência a Múltiplos Medicamentos
/
Proteínas de Ligação a DNA
/
Substâncias Intercalantes
/
Antibióticos Antineoplásicos
Tipo de estudo:
Diagnostic_studies
Limite:
Humans
Idioma:
En
Revista:
Leukemia
Assunto da revista:
HEMATOLOGIA
/
NEOPLASIAS
Ano de publicação:
1999
Tipo de documento:
Article
País de afiliação:
Holanda