Menna Pierantonio, Salvatorelli Emanuela, Minotti Giorgio
Unit of Drug Sciences, Department of Medicine, University Campus Bio-Medico , Via Alvaro del Portillo, 21, 00128 Rome, Italy.
Chem Res Toxicol. 2016 Aug 15;29(8):1270-8. doi: 10.1021/acs.chemrestox.6b00190. Epub 2016 Jul 22.
Pixantrone (6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione) has been approved by the European Medicines Agency for the treatment of refractory or relapsed non-Hodgkin's lymphoma (NHL). It is popularly referred to as a novel aza-anthracenedione, and as such it is grouped with anthracycline-like drugs. Preclinical development of pixantrone was in fact tailored to retain the same antitumor activity as that of anthracyclines or other anthracenediones while also avoiding cardiotoxicity that dose-limits clinical use of anthracycline-like drugs. Preliminary data in laboratory animals showed that pixantrone was active, primarily in hematologic malignancies, but caused significantly less cardiotoxicity than doxorubicin or mitoxantrone. Pixantrone was cardiac tolerable also in animals pretreated with doxorubicin, which anticipated a therapeutic niche for pixantrone to treat patients with a history of prior exposure to anthracyclines. This is the case for patients with refractory/relapsed NHL. Pixantrone clinical development, regulatory approval, and penetration in clinical practice were nonetheless laborious if not similar to a rocky road. Structural and nominal similarities with mitoxantrone and anthracyclines may have caused a negative influence, possibly leading to a general perception that pixantrone is a "me-too" anthracycline. Recent insights suggest this is not the case. Pixantrone shows pharmacological and toxicological mechanisms of action that are difficult to reconcile with anthracycline-like drugs. Pixantrone is a new drug with its own characteristics. For example, pixantrone causes mis-segregation of genomic material in cancer cells and inhibits formation of toxic anthracycline metabolites in cardiac cells. Understanding the differences between pixantrone and anthracyclines or mitoxantrone may help one to appreciate how it worked in the phase 3 study that led to its approval in Europe and how it might work in many more patients in everyday clinical practice, were it properly perceived as a drug with its own characteristics and therapeutic potential. The road is rocky but not a dead-end.
匹杉琼（6,9-双[(2-氨基乙基)氨基]苯并[g]异喹啉-5,10-二酮）已获欧洲药品管理局批准用于治疗难治性或复发性非霍奇金淋巴瘤（NHL）。它通常被称为新型氮杂蒽二酮，因此被归类为蒽环类药物。匹杉琼的临床前开发实际上是为了在保留与蒽环类药物或其他蒽二酮相同抗肿瘤活性的同时，避免蒽环类药物临床使用中剂量限制的心脏毒性。实验动物的初步数据表明，匹杉琼具有活性，主要针对血液系统恶性肿瘤，但其引起的心脏毒性明显低于多柔比星或米托蒽醌。在接受多柔比星预处理的动物中，匹杉琼对心脏也是可耐受的，这预示着匹杉琼在治疗有蒽环类药物既往暴露史患者方面具有治疗优势。难治性/复发性NHL患者就是这种情况。然而，匹杉琼的临床开发、监管批准以及在临床实践中的推广即便算不上崎岖坎坷，也是颇为费力的。与米托蒽醌和蒽环类药物在结构和名称上的相似性可能产生了负面影响，可能导致人们普遍认为匹杉琼是一种“me-too”蒽环类药物。最近的见解表明并非如此。匹杉琼显示出与蒽环类药物难以协调的药理和毒理作用机制。匹杉琼是一种具有自身特点的新药。例如，匹杉琼会导致癌细胞中基因组物质的错误分离，并抑制心脏细胞中有毒蒽环类代谢物的形成。了解匹杉琼与蒽环类药物或米托蒽醌之间的差异，可能有助于人们理解它在导致其在欧洲获批的3期研究中是如何发挥作用的，以及如果它被正确地视为一种具有自身特点和治疗潜力的药物，在日常临床实践中它可能如何在更多患者中发挥作用。道路虽崎岖，但并非死胡同。
