Martin Elke, Thougaard Annemette Vinding, Grauslund Morten, Jensen Peter B, Bjorkling Fredrik, Hasinoff Brian B, Tjørnelund Jette, Sehested Maxwell, Jensen Lars H
TopoTarget A/S, Symbion Science Park, Fruebjergvej 3, Copenhagen 2100, Denmark.
Toxicology. 2009 Jan 8;255(1-2):72-9. doi: 10.1016/j.tox.2008.10.011. Epub 2008 Oct 25.
Anthracycline-induced cardiomyopathy is a major problem in anti-cancer therapy. The only approved agent for alleviating this serious dose limiting side effect is ICRF-187 (dexrazoxane). The current thinking is that the ring-opened hydrolysis product of this agent, ADR-925, which is formed inside cardiomyocytes, removes iron from its complexes with anthracyclines, hereby reducing the concentration of highly toxic iron-anthracycline complexes that damage cardiomyocytes by semiquinone redox recycling and the production of free radicals. However, the 2 carbon linker ICRF-187 is also is a catalytic inhibitor of topoisomerase II, resulting in the risk of additional myelosuppression in patients receiving ICRF-187 as a cardioprotectant in combination with doxorubicin. The development of a topoisomerase II-inactive iron chelating compound thus appeared attractive. In the present paper we evaluate the topoisomerase II-inactive 3 carbon linker bisdioxopiperazine analog ICRF-161 as a cardioprotectant. We demonstrate that this compound does chelate iron and protects against doxorubicin-induced LDH release from primary rat cardiomyocytes in vitro, similarly to ICRF-187. The compound does not target topoisomerase II in vitro or in cells, it is well tolerated and shows similar exposure to ICRF-187 in rodents, and it does not induce myelosuppression when given at high doses to mice as opposed to ICRF-187. However, when tested in a model of chronic anthracycline-induced cardiomyopathy in spontaneously hypertensive rats, ICRF-161 was not capable of protecting against the cardiotoxic effects of doxorubicin. Modulation of the activity of the beta isoform of the topoisomerase II enzyme by ICRF-187 has recently been proposed as the mechanism behind its cardioprotection. This concept is thus supported by the present study in that iron chelation alone does not appear to be sufficient for protection against anthracycline-induced cardiomyopathy.
蒽环类药物诱导的心肌病是抗癌治疗中的一个主要问题。唯一被批准用于缓解这种严重剂量限制副作用的药物是ICRF-187（右丙亚胺）。目前的观点认为，该药物在心肌细胞内形成的开环水解产物ADR-925，会从其与蒽环类药物的复合物中去除铁，从而降低通过半醌氧化还原循环和自由基产生而损害心肌细胞的高毒性铁-蒽环类药物复合物的浓度。然而，ICRF-187的2碳连接体也是拓扑异构酶II的催化抑制剂，这导致接受ICRF-187作为心脏保护剂与多柔比星联合使用的患者有额外骨髓抑制的风险。因此，开发一种无拓扑异构酶II活性的铁螯合化合物似乎很有吸引力。在本文中，我们评估了无拓扑异构酶II活性的3碳连接体双二氧哌嗪类似物ICRF-161作为心脏保护剂的作用。我们证明，该化合物确实能螯合铁，并在体外保护原代大鼠心肌细胞免受多柔比星诱导的乳酸脱氢酶释放，这与ICRF-187类似。该化合物在体外或细胞中不作用于拓扑异构酶II，耐受性良好，在啮齿动物中的暴露情况与ICRF-187相似，并且与ICRF-187不同，高剂量给予小鼠时不会诱导骨髓抑制。然而，在自发性高血压大鼠的慢性蒽环类药物诱导的心肌病模型中进行测试时，ICRF-161无法预防多柔比星的心脏毒性作用。最近有人提出，ICRF-187对拓扑异构酶II酶β异构体活性的调节是其心脏保护作用背后的机制。因此，本研究支持了这一概念，即仅铁螯合似乎不足以预防蒽环类药物诱导的心肌病。
