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

P-glycoprotein(P-gp)- related resistance is one of the major obstacles in t reating leukemia patients. Therefore, it is of clinical interest to find ne w potential modulators and compare their P-gp-modulating efficacy The prese nt analysis investigated the influence of P-gp modulators, such as verapami l, tamoxifen, droloxifene E, droloxifene Z, SDZ PSC 833 (PSC 833) and dexni guldipine in a leukemic T-cell line (CCRF-CEM) and its P-gp-resistant count erparts (CCRF-CEM/ACT400 and CCRF-CEM/VCR1000). P-gp expression was assesse d with an immunocytological technique using the monoclonal antibody 4E3.16. It was characterized as the percentage of P-gp positive cells and also exp ressed 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 mu M and 3 mu M was determined, where no genuine antiproliferative effect was appar ent. The modulators PSC 833 and dexniguldipine were the significant (p < C0 .05) most potent chemosensitizers followed by verapamil, droloxifene Z, tam oxifen 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 o f droloxifene Z could be the low rate of expected side effects. This fact p ermits the use of high Drol Z dosage in order to achieve a relevant modulat ing effect in vivo and to use this drug in combination with a further modul ator so as to reach maximum efficacy with tolerable side effects.