Treatment results for multiple myeloma and plasma cell leukemia have considerably improved, but cure remains elusive and establishing new therapeutic approaches constitutes a major unmet clinical need. We analyzed the anti-myeloma properties of the aza-anthracenedione pixantrone which has been successfully used in a phase III study for the treatment of patients with aggressive non-Hodgkin's lymphoma as monotherapy as well as in combination regimes in vitro and in an adapted in vivo model (ex ovo chicken chorioallantoic membrane (CAM) assay). Pixantrone significantly inhibited proliferation and metabolic activity of all investigated myeloma cell lines. Importantly, anti-myeloma effects were more pronounced in tumor cell lines than in stromal cells, mesenchymal stem cells, and peripheral blood mononuclear cells of healthy controls. Apoptosis of myeloma cell lines was observed only after a 7-day incubation period, indicating a fast cytostatic and a slower cytotoxic effect of this drug. Pixantrone reduced the viability of primary plasma cells of patients and induced downregulation of myeloma-cell growth in the CAM assay. Additionally, we demonstrate in vitro synergism between pixantrone and the histone deacetylase inhibitor panobinostat with respect to its anti-proliferative features. From these data, we conclude that systematic investigations of the clinical usefulness of pixantrone in the framework of controlled clinical trials are clearly indicated (e.g., in penta-refractory patients).

中文翻译：

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吡咯酮显示出对多发性骨髓瘤和浆细胞白血病的显着体外活性。

多发性骨髓瘤和浆细胞性白血病的治疗效果已有显着改善，但治愈仍然难以捉摸，建立新的治疗方法构成了主要的未满足临床需求。我们分析了氮杂蒽酮二酮匹克蒽酮的抗骨髓瘤特性，该化合物已成功用于III期研究，用于治疗侵袭性非霍奇金淋巴瘤的患者作为单一疗法以及在体外和适应性体内联合治疗中的应用模型（卵内鸡绒膜尿囊膜（CAM）分析）。吡咯烷酮显着抑制所有研究的骨髓瘤细胞系的增殖和代谢活性。重要的是，在健康细胞中，抗​​骨髓瘤的作用在肿瘤细胞系中比在基质细胞，间充质干细胞和外周血单核细胞中更为明显。仅在7天的温育期后才观察到骨髓瘤细胞系的凋亡，表明该药物具有快速的细胞抑制作用和较慢的细胞毒性作用。吡咯烷酮降低了患者原代浆细胞的活力，并在CAM分析中诱导了骨髓瘤细胞生长的下调。此外，我们证明了pixantrone和组蛋白脱乙酰基酶抑制剂panobinostat之间的体外协同作用具有抗增殖功能。从这些数据中，我们得出结论，明确指出了在对照临床试验框架内对吡咯烷酮的临床有效性进行系统研究（例如，在难治性五角大楼患者中）。吡咯烷酮降低了患者原代浆细胞的活力，并在CAM分析中诱导了骨髓瘤细胞生长的下调。此外，我们证明了pixantrone和组蛋白脱乙酰基酶抑制剂panobinostat之间的体外协同作用具有抗增殖功能。从这些数据中，我们得出结论，明确指出了在对照临床试验框架内对吡咯烷酮的临床有效性进行系统研究（例如，在难治性五角大楼患者中）。吡咯烷酮降低了患者原代浆细胞的活力，并在CAM分析中诱导了骨髓瘤细胞生长的下调。此外，我们证明了pixantrone和组蛋白脱乙酰基酶抑制剂panobinostat之间的体外协同作用具有抗增殖功能。从这些数据中，我们得出结论，明确指出了在对照临床试验框架内对吡咯烷酮的临床有效性进行系统研究（例如，在难治性五角大楼患者中）。