Takeshita A, Shinjo K, Naito K, Matsui H, Sahara N, Shigeno K, Horii T, Shirai N, Maekawa M, Ohnishi K, Naoe T, Ohno R
Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Leukemia. 2005 Aug;19(8):1306-11. doi: 10.1038/sj.leu.2403807.
Acute promyelocytic leukemia (APL) cells express a considerable level of CD33, which is a target of gemtuzumab ozogamicin (GO), and a significantly lower level of P-glycoprotein (P-gp). In this study, we examined whether GO was effective on all-trans retinoic acid (ATRA)- or arsenic trioxide (ATO)-resistant APL cells. Cells used were an APL cell line in which P-gp was undetectable (NB4), ATRA-resistant NB4 (NB4/RA), NB4 and NB4/RA that had been transfected with MDR-1 cDNA (NB4/MDR and NB4/RA/MDR, respectively), ATO-resistant NB4 (NB4/As) and blast cells from eight patients with clinically ATRA-resistant APL including two patients with ATRA- and ATO-resistant APL. The efficacy of GO was analyzed by (3)H-thymidine incorporation, the dye exclusion test and cell cycle distribution. GO suppressed the growth of NB4, NB4/RA and NB4/As cells in a dose-dependent manner. GO increased the percentage of hypodiploid cells significantly in NB4, NB4/RA and NB4/As cells, and by a limited degree in NB4/MDR and NB4/RA/MDR cells. Similar results were obtained using blast cells from the patients with APL. GO is effective against ATRA- or ATO-resistant APL cells that do not express P-gp, and the mechanism of resistance to GO is not related to the mechanism of resistance to ATRA or ATO in APL cells. Leukemia (2005) 19, 1306-1311. doi:10.1038/sj.leu.2403807; published online 26 May 2005.
急性早幼粒细胞白血病（APL）细胞表达相当高水平的CD33，其是吉妥单抗奥唑米星（GO）的靶点，而P-糖蛋白（P-gp）水平则显著较低。在本研究中，我们检测了GO对全反式维甲酸（ATRA）或三氧化二砷（ATO）耐药的APL细胞是否有效。所用细胞为P-gp检测不到的APL细胞系（NB4）、对ATRA耐药的NB4（NB4/RA）、转染了MDR-1 cDNA的NB4和NB4/RA（分别为NB4/MDR和NB4/RA/MDR）、对ATO耐药的NB4（NB4/As）以及来自8例临床ATRA耐药APL患者的原始细胞，其中包括2例对ATRA和ATO均耐药的APL患者。通过³H-胸腺嘧啶核苷掺入、染料排除试验和细胞周期分布分析GO的疗效。GO以剂量依赖方式抑制NB4、NB4/RA和NB4/As细胞的生长。GO使NB4、NB4/RA和NB4/As细胞中次二倍体细胞百分比显著增加，而在NB4/MDR和NB4/RA/MDR细胞中增加程度有限。使用APL患者的原始细胞也获得了类似结果。GO对不表达P-gp的ATRA或ATO耐药的APL细胞有效，且APL细胞对GO的耐药机制与对ATRA或ATO的耐药机制无关。《白血病》（2005年）19卷，1306 - 1311页。doi:10.1038/sj.leu.2403807；2005年5月26日在线发表。
