Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, 3311-Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.
Anticancer Res. 2009 Nov;29(11):4589-96.
The CD33 antigen is expressed on leukemia cells in most patients with acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL), and in 20% of patients with acute lymphoblastic leukemia (ALL), while it is absent from pluripotent hematopoietic stem cells and nonhematopoietic cells. Gemtuzumab ozogamicin (GO) is an immunoconjugate of an anti-CD33 antibody linked to calicheamicin, which is a potent cytotoxic agent that causes double-strand DNA breaks, resulting in cell death. GO was developed against CD33 antigen-positive leukemias. The aim of this study was to investigate the cytotoxic effects of this agent in combination with conventional antileukemic agents.
The cytotoxic effects of GO in combination with antileukemic agents were studied against human CD33 antigen-positive leukemia HL-60, U937, TCC-S and NALM20 cells. The leukemia cells were exposed simultaneously to GO and to the other agents for 4 days. Cell growth inhibition was determined using a MTT reduction assay. The isobologram method was used to evaluate the cytotoxic interaction.
GO produced synergistic effects with mitoxantrone, additive effects with cytarabine, daunorubicin, idarubicin, doxorubicin, etoposide and 6-mercaptopurine, and antagonistic effects with methotrexate and vincristine.
Our findings suggest that the simultaneous administration of GO with most agents studied would be advantageous for antileukemic activity. The simultaneous administration of GO with methotrexate or vincristine would have little cytotoxic effect, and this combination may be inappropriate. These findings may be useful in clinical trials of combination chemotherapy including GO or other monoclonal antibodies linked to calicheamicin.
CD33 抗原在大多数急性髓细胞白血病（AML）和急性早幼粒细胞白血病（APL）患者的白血病细胞中表达，在 20%的急性淋巴细胞白血病（ALL）患者中表达，而在多能造血干细胞和非造血细胞中则不存在。吉妥珠单抗奥佐米星（GO）是一种抗 CD33 抗体与加利车霉素连接而成的免疫偶联物，加利车霉素是一种有效的细胞毒性剂，可导致双链 DNA 断裂，从而导致细胞死亡。GO 是针对 CD33 抗原阳性白血病而开发的。本研究旨在研究该药物与常规抗白血病药物联合使用的细胞毒性作用。
研究了 GO 与抗白血病药物联合使用对人 CD33 抗原阳性白血病 HL-60、U937、TCC-S 和 NALM20 细胞的细胞毒性作用。白血病细胞同时暴露于 GO 和其他药物 4 天。使用 MTT 还原测定法测定细胞生长抑制率。采用等对数图法评价细胞毒性相互作用。
GO 与米托蒽醌产生协同作用，与阿糖胞苷、柔红霉素、伊达比星、多柔比星、依托泊苷和 6-巯基嘌呤产生相加作用，与甲氨蝶呤和长春新碱产生拮抗作用。
我们的研究结果表明，GO 与大多数研究中的药物同时给药将有利于抗白血病活性。GO 与甲氨蝶呤或长春新碱同时给药的细胞毒性作用很小，这种组合可能不合适。这些发现可能对包括 GO 或其他与加利车霉素连接的单克隆抗体在内的联合化疗临床试验有用。
