Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
Drug Discovery Laboratory, Wakunaga Pharmaceutical Co., Ltd, Hiroshima, Japan.
Invest New Drugs. 2023 Oct;41(5):751-760. doi: 10.1007/s10637-023-01393-0. Epub 2023 Sep 13.
Approximately 60%-80% of patients who achieve complete remission eventually relapse after conventional chemotherapy and have poor prognoses despite the recent advances of novel anticancer agents. Continuing development of more effective novel treatments for acute myeloid leukemia (AML) is necessary. We developed (R)-WAC-224 (R-WAC), which is an anticancer quinolone, targeting topoisomerase II. This study evaluated the anti-leukemia potential of R-WAC or racemic WAC-224 (WAC) in vitro and in vivo. R-WAC significantly inhibited the human AML cell line proliferation (MV4-11, HL60, and KG1a), which was comparable to daunorubicin and cytarabine, not affected by P-glycoprotein overexpression. WAC did neither increase serum troponin-T nor decrease the crypt numbers in the small intestine, indicating WAC was less toxic than doxorubicin. R-WAC monotherapy demonstrated prolonged survival in the AML mice model and inhibited tumor growth in the MV4-11 xenograft mice model. Moreover, the combination of R-WAC and cytarabine demonstrated more active anti-leukemia effects than daunorubicin and cytarabine. Finally, R-WAC inhibited the colony-forming abilities using primary AML cells. These results indicate that R-WAC is a promising therapeutic agent for AML.
约 60%-80%的患者在接受常规化疗后达到完全缓解，但最终仍会复发，且预后较差，尽管新型抗癌药物最近有所进展。因此，有必要继续开发更有效的新型急性髓细胞白血病 (AML) 治疗方法。我们开发了（R）-WAC-224（R-WAC），这是一种针对拓扑异构酶 II 的抗癌喹诺酮。本研究评估了 R-WAC 或外消旋 WAC-224（WAC）在体外和体内的抗白血病潜力。R-WAC 显著抑制人 AML 细胞系的增殖（MV4-11、HL60 和 KG1a），与柔红霉素和阿糖胞苷相当，不受 P-糖蛋白过表达的影响。WAC 既不增加血清肌钙蛋白-T，也不减少小肠隐窝数量，表明 WAC 的毒性小于多柔比星。R-WAC 单药治疗可延长 AML 小鼠模型的存活时间，并抑制 MV4-11 异种移植小鼠模型中的肿瘤生长。此外，R-WAC 联合阿糖胞苷的抗白血病效果比柔红霉素和阿糖胞苷更显著。最后，R-WAC 抑制了原代 AML 细胞的集落形成能力。这些结果表明，R-WAC 是一种有前途的 AML 治疗药物。
