Zhou D C, Simonin G, Faussat A M, Zittoun R, Marie J P
Laboratoire de Cinétique et Cultures Cellulaires, Université Paris VI, and Formation de Recherche Associée Claude Bernard, Hôtel Dieu de Paris, France.
Leukemia. 1997 Sep;11(9):1516-22. doi: 10.1038/sj.leu.2400761.
The drug GG918 has been specifically developed for overcoming MDR phenotype and is now in use in clinical trials. In this study, the effects of GG918 on leukemic cell were investigated using a 3 day MTT assay. Results showed that, in a highly resistant P-gp(+) leukemic cell line, 0.1 microM of GG918 gives rise to a 40-fold sensitization to daunorubicin (DNR) (residual resistance: 2.1), a 57-fold sensitization to mitoxantrone (residual resistance: 1.5), and a 3.3-fold sensitization to idarubicin (residual resistance: 2.9). When human AB serum was added to the incubation medium, 1 microM of GG918 was needed to observe the full P-gp modulation potency described above. The effect of 1 microM of GG918 was tested on 27 samples of poor prognosis acute leukemia (25 AML, two ALL). DNR sensitization (using the MTT assay) and modulation of rhodamine 123 uptake were monitored and used as criteria for comparing the in vitro modulation potency of this new compound to the potency of 10 microM of verapamil, which was used as reference. A good correlation (r = 0.8, P = 0.001) was observed between the results of the two tests. Eleven out of the 26 cases tested were MDR1(+) (42%), and showed a higher IC50 for DNR than the negative cases (861 +/- 1284 nM vs 187 +/- 246 nM, P = 0.05). GG918 was able to modulate the in vitro resistance to DNR in eight cases (seven MDR1(+), no MDR1(-), one non-tested). Verapamil did not increase DNR toxicity in four of these eight cases, but was more efficient in one other MDR1(+) case. In conclusion, the DNR sensitivity of the majority of the fresh AML samples expressing P-gp could be modulated in vitro by 1 microM of GG918.
药物GG918是专门为克服多药耐药（MDR）表型而研发的，目前正用于临床试验。在本研究中，采用为期3天的MTT试验研究了GG918对白血病细胞的作用。结果显示，在一种高度耐药的P-糖蛋白（P-gp）阳性白血病细胞系中，0.1微摩尔/升的GG918可使柔红霉素（DNR）的敏感性提高40倍（残余耐药性：2.1），使米托蒽醌的敏感性提高57倍（残余耐药性：1.5），使伊达比星的敏感性提高3.3倍（残余耐药性：2.9）。当向孵育培养基中加入人AB血清时，需要1微摩尔/升的GG918才能观察到上述完整的P-gp调节效力。对27例预后不良的急性白血病样本（25例急性髓系白血病，2例急性淋巴细胞白血病）测试了1微摩尔/升GG918的效果。监测DNR敏感性（采用MTT试验）和罗丹明123摄取的调节情况，并将其作为比较该新化合物与作为参照的10微摩尔/升维拉帕米体外调节效力的标准。两项试验结果之间观察到良好的相关性（r = 0.8，P = 0.001）。在26例受试病例中，11例为多药耐药基因1（MDR1）阳性（42%），其DNR的半数抑制浓度（IC50）高于阴性病例（861±1284纳摩尔/升对187±246纳摩尔/升，P = 0.05）。GG918能够在8例病例中调节对DNR的体外耐药性（7例MDR1阳性，无MDR1阴性，1例未检测）。在这8例病例中的4例中，维拉帕米未增加DNR毒性，但在另一例MDR1阳性病例中更有效。总之，1微摩尔/升的GG918能够在体外调节大多数表达P-gp的新鲜急性髓系白血病样本对DNR的敏感性。
