Abstract:
PURPOSE:Novel multidrug resistance (mdr) modulators have been proved as inhibitors of P-glycoprotein (P-gp). We first investigated the in vitro effects of selected compounds in human cancer cells on multidrug resistance reversal effects compared to drug standards and on P-gp induction to characterize the potential of the compounds as clinical candidates. METHODS:The uptake of daunorubicin into a parental cancer cell line and P-gp expressing subcell line in presence of the modulators was characterized by flow cytometry. Induction of P-gp was investigated in P-gp expressing and non-expressing cancer cell lines on the RNA level by real-time quantitative polymerase chain reaction (RTQ-PCR) and protein quantification. Results were additionally confirmed by northern blot techniques and functionality assays in selected cell lines. RESULTS:The novel modulators showed activities as mdr reversers in a P-gp specific human cancer cell model with mainly increased uptake rates of daunorubicin into the drug-resistant cell line. H17 proved to be more active than cyclosporine A as a known strong mdr modulator. The induction studies revealed practically no induction potential of the compounds in usual short-time drug application regimes in all cell lines. Furthermore, the novel modulators did not increase the efflux of a P-gp model substrate in the functionality model assay. This confirmed the results of non-P-gp induction which was observed on both the RNA and the protein levels. CONCLUSIONS:The novel mdr modulators proved as perspective candidates for further clinical studies because they turned out to be highly active in human cancer cell models. Furthermore, they showed no potential to induce the transmembrane efflux pump P-gp. This is a significant advantage compared to modulators which failed in clinical trials because of induction-effects that increase cellular resistances and, moreover, side effects in normal cells.
journal_name
Pharm Resjournal_title
Pharmaceutical researchauthors
Coburger C,Lage H,Molnár J,Hilgeroth Adoi
10.1007/s11095-008-9736-7subject
Has Abstractpub_date
2009-01-01 00:00:00pages
182-8issue
1eissn
0724-8741issn
1573-904Xjournal_volume
26pub_type
杂志文章abstract::Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring anti-inflammatory antagonist of interleukin-1 family of pro-inflammatory cytokines. The broad spectrum anti-inflammatory effects of IL-1Ra have been investigated against various auto-immune diseases such as diabetes mellitus, rheumatoid arthritis. Des...
journal_title:Pharmaceutical research
pub_type: 杂志文章,评审
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journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1018938722768
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journal_title:Pharmaceutical research
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journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-010-0337-x
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journal_title:Pharmaceutical research
pub_type: 杂志文章
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journal_title:Pharmaceutical research
pub_type: 杂志文章
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abstract::The application of supercritical fluid (SF) processing in pharmaceutical research is increasing particularly in the field of particle formation for drug delivery systems. The SF processes have benefits over the existing particle formation methods in terms of improved control, flexibility and operational ease. This rev...
journal_title:Pharmaceutical research
pub_type: 杂志文章,评审
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journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1016002606705
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journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1016061330387
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journal_title:Pharmaceutical research
pub_type: 杂志文章
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journal_title:Pharmaceutical research
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更新日期:2006-04-01 00:00:00
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更新日期:2004-10-01 00:00:00
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pub_type: 杂志文章
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更新日期:1997-11-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-005-4591-2
更新日期:2005-06-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1023/a:1015880218535
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journal_title:Pharmaceutical research
pub_type: 杂志文章
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journal_title:Pharmaceutical research
pub_type: 杂志文章,评审
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更新日期:2011-08-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
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更新日期:2005-07-01 00:00:00
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journal_title:Pharmaceutical research
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更新日期:2012-10-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-011-0553-z
更新日期:2012-01-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-010-0277-5
更新日期:2010-12-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
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更新日期:1998-07-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
doi:10.1007/s11095-005-4581-4
更新日期:2005-06-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 杂志文章
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更新日期:2010-07-01 00:00:00
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journal_title:Pharmaceutical research
pub_type: 临床试验,杂志文章
doi:10.1023/a:1016040825844
更新日期:1996-06-01 00:00:00