Intermittent exposure to doxorubicin in vitro selects for multifactorial non-P-glycoprotein-associated multidrug resistance in RPMI 8226 human myeloma cells.
Br J Haematol
; 97(1): 65-75, 1997 Apr.
Article
em En
| MEDLINE
| ID: mdl-9136943
ABSTRACT
The purpose of the present study was to evaluate whether intermittent exposure to a constant dose of doxorubicin selects for multidrug resistance (MDR) in RPMI 8226 human myeloma cells and, if so, to determine the molecular mechanism. In an attempt to approximate clinical doxorubicin treatment in vitro, cells were exposed to a fixed dose of doxorubicin for 4 d alternating with growth in drug-free medium for 17 d. An MDR subline emerged, termed 8226/DOXint5, which was 3-4-fold resistant to doxorubicin, etoposide and m-AMSA, and 1.6-fold resistant to vincristine. Sensitivity to docetaxel, melphalan and cisplatin was normal. Verapamil normalized vincristine sensitivity but had little effect on resistance to the other agents. Cellular uptake and retention of daunorubicin and vincristine were reduced by approximately 10%. The 8226/DOXint5 cells showed diminished DNA topoisomerase IIalpha expression and increased expression of the multidrug resistance protein MRP. Expression of MDR1/P-glycoprotein was not detected. Immunostaining showed 70% of the cells to over-express the lung-resistance protein LRP. This new MDR myeloma cell line may prove to be a useful model for the development of strategies to overcome low-level, multifactorial MDR, which might be a common phenomenon in clinical myeloma treated with doxorubicin.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doxorrubicina
/
Membro 1 da Subfamília B de Cassetes de Ligação de ATP
/
Antibióticos Antineoplásicos
/
Mieloma Múltiplo
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Br J Haematol
Ano de publicação:
1997
Tipo de documento:
Article
País de afiliação:
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