Takeshita Akihiro, Shinjo Kaori, Yamakage Nozomi, Ono Takaaki, Hirano Isao, Matsui Hirotaka, Shigeno Kazuyuki, Nakamura Satoki, Tobita Tadasu, Maekawa Masato, Ohnishi Kazunori, Sugimoto Yoshikazu, Kiyoi Hitoshi, Naoe Tomoki, Ohno Ryuzo
Laboratory and Internal Medicine, Hamamatsu University School of Medicine, Higashiku, Hamamatsu, Japan.
Br J Haematol. 2009 Jun;146(1):34-43. doi: 10.1111/j.1365-2141.2009.07701.x. Epub 2009 Apr 13.
The effect of CMC-544, a calicheamicin-conjugated anti-CD22 monoclonal antibody, was analysed in relation to CD22 and P-glycoprotein (P-gp) in B-cell chronic lymphocytic leukaemia (CLL) and non-Hodgkin lymphoma (NHL) in vitro. The cell lines used were CD22-positive parental Daudi and Raji, and their P-gp positive sublines, Daudi/MDR and Raji/MDR. Cells obtained from 19 patients with B-cell CLL or NHL were also used. The effect of CMC-544 was analysed by viable cell count, morphology, annexin-V staining, and cell cycle distribution. A dose-dependent, selective cytotoxic effect of CMC-544 was observed in cell lines that expressed CD22. CMC-544 was not effective on Daudi/MDR and Raji/MDR cells compared with their parental cells. The MDR modifiers, PSC833 and MS209, restored the cytotoxic effect of CMC-544 in P-gp-expressing sublines. In clinical samples, the cytotoxic effect of CMC-544 was inversely related to the amount of P-gp (P = 0.003), and to intracellular rhodamine-123 accumulation (P < 0.001). On the other hand, the effect positively correlated with the amount of CD22 (P = 0.010). The effect of CMC-544 depends on the levels of CD22 and P-gp. Our findings will help to predict the clinical effectiveness of this drug on these B-cell malignancies, suggesting a beneficial effect with combined use of CMC-544 and MDR modifiers.
在体外对一种与刺孢霉素偶联的抗CD22单克隆抗体CMC-544针对B细胞慢性淋巴细胞白血病（CLL）和非霍奇金淋巴瘤（NHL）中的CD22和P-糖蛋白（P-gp）的作用进行了分析。所使用的细胞系为CD22阳性的亲本细胞系Daudi和Raji，以及它们的P-gp阳性亚系Daudi/MDR和Raji/MDR。还使用了从19例B细胞CLL或NHL患者获得的细胞。通过活细胞计数、形态学、膜联蛋白V染色和细胞周期分布来分析CMC-544的作用。在表达CD22的细胞系中观察到CMC-544呈剂量依赖性的选择性细胞毒性作用。与亲本细胞相比，CMC-544对Daudi/MDR和Raji/MDR细胞无效。多药耐药调节剂PSC833和MS209恢复了CMC-544在表达P-gp的亚系中的细胞毒性作用。在临床样本中，CMC-544的细胞毒性作用与P-gp的量呈负相关（P = 0.003），与细胞内罗丹明123的蓄积呈负相关（P < 0.001）。另一方面，该作用与CD22的量呈正相关（P = 0.010）。CMC-544的作用取决于CD22和P-gp的水平。我们的研究结果将有助于预测该药物对这些B细胞恶性肿瘤的临床疗效，提示联合使用CMC-544和多药耐药调节剂具有有益作用。
