In vitro efficacy of known P-glycoprotein modulators compared to droloxifene E and Z: studies on a human T-cell leukemia cell line and their resistant variants.

Abstract

P-glycoprotein(P-gp)- related resistance is one of the major obstacles in treating leukemia patients. Therefore, it is of clinical interest to find new potential modulators and compare their P-gp-modulating efficacy. The present analysis investigated the influence of P-gp modulators, such as verapamil, tamoxifen, droloxifene E, droloxifene Z, SDZ PSC 833 (PSC 833) and dexniguldipine in a leukemic T-cell line (CCRF-CEM) and its P-gp-resistant counterparts (CCRF-CEM/ACT400 and CCRF-CEM/VCR1000). P-gp expression was assessed with an immunocytological technique using the monoclonal antibody 4E3.16. It was characterized as the percentage of P-gp positive cells and also expressed as a D value by using the Kolmogorov Smirnov statistic. The efficacy of P-gp modulators was determined with the rhodamine-123 accumulation test and the MTT test. An in vitro modulator concentration between 0.1 microM and 3 microM was determined, where no genuine antiproliferative effect was apparent. The modulators PSC 833 and dexniguldipine were the significant (p<C0.05) most potent chemosensitizers followed by verapamil, droloxifene Z, tamoxifen and droloxifene E in descending order. In addition to the modulators PSC 833 and dexniguldipine, droloxifene Z should especially be considered as a candidate for future ex vivo and in vivo studies. The main advantage of droloxifene Z could be the low rate of expected side effects. This fact permits the use of high Drol Z dosage in order to achieve a relevant modulating effect in vivo and to use this drug in combination with a further modulator so as to reach maximum efficacy with tolerable side effects.

• Authors: V Nüssler, R Pelka-Fleisc, F Gieseler, M Hasmann, R Löser, E Gullis, O Stötzer, H Zwierzina, W Wilmanns
• Journal: Leukemia & lymphoma (Leuk Lymphoma) Vol. 31 Issue 5-6 Pg. 589-97 (Nov 1998) ISSN: 1042-8194 [Print] United States
• PMID: 9922050 (Publication Type: Comparative Study, Journal Article)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• ATP-Binding Cassette Transporters
• Antibodies, Monoclonal
• Cyclosporins
• Dihydropyridines
• Multidrug Resistance-Associated Proteins
• Neoplasm Proteins
• Vault Ribonucleoprotein Particles
• major vault protein
• Tamoxifen
• droloxifene
• Verapamil
• valspodar
• niguldipine

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors)
• ATP-Binding Cassette Transporters (analysis)
• Antibodies, Monoclonal (immunology)
• Cell Division (drug effects)
• Cyclosporins (pharmacology)
• Dihydropyridines (pharmacology)
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Drug Screening Assays, Antitumor
• Humans
• Leukemia, T-Cell (pathology)
• Multidrug Resistance-Associated Proteins
• Neoplasm Proteins (antagonists & inhibitors)
• Tamoxifen (analogs & derivatives, pharmacology)
• Tumor Cells, Cultured (drug effects)
• Vault Ribonucleoprotein Particles
• Verapamil (pharmacology)