Matsui H, Takeshita A, Naito K, Shinjo K, Shigeno K, Maekawa M, Yamakawa Y, Tanimoto M, Kobayashi M, Ohnishi K, Ohno R
Division of Hematology, Department of Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Hamamatsu-shi, 431-3192 Japan.
Leukemia. 2002 May;16(5):813-9. doi: 10.1038/sj.leu.2402459.
Gemtuzumab ozogamicin (CMA-676), a calicheamicin-conjugated humanized anti-CD33 mouse monoclonal antibody, has recently been introduced clinically as a promising drug for the treatment of patients with acute myeloid leukemia (AML), more than 90% of which express CD33 antigen. However, our recent study suggested that CMA-676 was excreted by a multi- drug-resistance (MDR) mechanism in P-glycoprotein (P-gp)-expressing leukemia cell lines. We analyzed the in vitro effects of CMA-676 on leukemia cells from 27 AML patients in relation to the amount of P-gp, MDR-associated protein 1 (MRP1), CD33 and CD34, using a multi-laser-equipped flow cytometer. The cytocidal effect of CMA-676, estimated by the amount of hypodiploid portion on cell cycle, was inversely related to the amount of P-gp estimated by MRK16 monoclonal antibody (P = 0.004), and to the P-gp function assessed by intracellular rhodamine-123 accumulation in the presence of PSC833 or MS209 as a MDR modifier (P = 0.0004 and P = 0.002, respectively). In addition, these MDR modifiers reversed CMA-676 resistance in P-gp-expressing CD33(+) leukemia cells (P = 0.001 with PSC833 and P = 0.0007 with MS209). In CD33(+) AML cells from 13 patients, CMA-676 was less effective on CD33(+)CD34(+) than CD33(+)CD34(-) cells (P = 0.002). PSC833 partially restored the effect of CMA-676 in CD33(+)CD34(+) cells. These results suggest that the combined use of CMA-676 and a MDR modifier will be more effective on CD33(+) AML with P-gp-related MDR.
吉妥单抗奥佐米星（CMA-676）是一种与加利车霉素偶联的人源化抗CD33小鼠单克隆抗体，最近已作为一种有前景的药物引入临床，用于治疗急性髓系白血病（AML）患者，其中超过90%的患者表达CD33抗原。然而，我们最近的研究表明，CMA-676在表达P-糖蛋白（P-gp）的白血病细胞系中通过多药耐药（MDR）机制排泄。我们使用配备多激光的流式细胞仪分析了CMA-676对27例AML患者白血病细胞的体外作用，这些作用与P-gp、多药耐药相关蛋白1（MRP1）、CD33和CD34的量有关。通过细胞周期中次二倍体部分的量估计的CMA-676的杀细胞作用与通过MRK16单克隆抗体估计的P-gp的量呈负相关（P = 0.004），并且与在作为MDR调节剂的PSC833或MS209存在下通过细胞内罗丹明-123积累评估的P-gp功能呈负相关（分别为P = 0.0004和P = 0.002）。此外，这些MDR调节剂逆转了表达P-gp的CD33(+)白血病细胞对CMA-676的耐药性（使用PSC833时P = 0.001，使用MS209时P = 0.0007）。在13例患者的CD33(+) AML细胞中，CMA-676对CD33(+)CD34(+)细胞的作用比对CD33(+)CD34(-)细胞的作用小（P = 0.002）。PSC833部分恢复了CMA-676在CD33(+)CD34(+)细胞中的作用。这些结果表明，CMA-676与MDR调节剂联合使用对具有P-gp相关MDR的CD33(+) AML将更有效。
