Development of novel reversal agents, imidazothiazole derivatives, targeting MDR1- and MRP-mediated multidrug resistance.
Oncol Res
; 10(3): 123-32, 1998.
Article
em En
| MEDLINE
| ID: mdl-9700723
ABSTRACT
Three newly synthesized imidazothiazole derivatives (N276-12, N276-14, N276-17) were examined regarding their ability and mechanism as a chemosensitizing agent against multidrug resistance 1 (MDR1)-mediated and multidrug resistance-associated protein (MRP)-mediated MDR. All three N276 compounds almost completely reversed the acquired resistance to vincristine (VCR), vinblastine (VBL), and doxorubicin (DXR) in MDR1-overexpressing human cancer cell lines (KB/VJ300 and T24/VCR). Their reversal effect against acquired resistance to VCR, DXR, and etoposide (VP16) was partial but clearly observed in the cell line expressing MRP (KB/VP4). All three N276 compounds enhanced the intracellular accumulation of [3H]VCR in MDR1-overexpressing KB/VJ300 cells through the inhibition of the increased efflux of the drug. They (100 microM) almost completely inhibited the photoaffinity labeling of P-glycoprotein encoded by the MDR1 gene. All the N276 compounds also remarkably enhanced the sensitivity to VBL and DXR in both MDR1- and MRP-overexpressing renal cell carcinoma (RCC) cell line (NKK1), whereas they showed no potentiation of these anticancer agents in an RCC cell line (KPK1) expressing neither MDR1 nor MRP. The combination chemotherapy of VCR or VP16 with N276-12 significantly increased the life span of mice inoculated i.p. or i.v. with drug-resistant P388/VCR cells without any significant side effects, whereas chemotherapy with the anticancer agent alone did not increase the life span at all. These results suggest that these newly synthesized imidazothiazole derivatives can be a useful chemosensitizing agent against not only MDR1- but also MRP-mediated MDR.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tiazóis
/
Resistência a Múltiplos Medicamentos
/
Transportadores de Cassetes de Ligação de ATP
/
Proteínas Associadas à Resistência a Múltiplos Medicamentos
/
Imidazóis
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Oncol Res
Assunto da revista:
NEOPLASIAS
Ano de publicação:
1998
Tipo de documento:
Article
País de afiliação:
Japão