TopoTarget A/S, Symbion Science Park, Fruebjergvej 3, 2100 Copenhagen, Denmark.
Toxicology. 2010 Feb 28;269(1):67-72. doi: 10.1016/j.tox.2010.01.007. Epub 2010 Jan 15.
The bisdioxopiperazine topoisomerase II catalytic inhibitor dexrazoxane has successfully been introduced into the clinic as an antidote to accidental anthracycline extravasation based on our preclinical mouse studies. The histology of this mouse extravasation model was investigated and found to be similar to findings in humans: massive necrosis in the subcutis, dermis and epidermis followed by sequestration and healing with granulation tissue, and a graft-versus-host-like reaction with hyperkeratotic and acanthotic keratinocytes, occasional apoptoses, epidermal invasion by lymphocytes and healing with dense dermal connective tissue. The extension of this fibrosis was quantified, and dexrazoxane intervention resulted in a statistically significant decrease in fibrosis extension, as also observed in the clinic. Several mechanisms have been proposed in anthracycline extravasation cytotoxicity, and we tested two major hypotheses: (1) interaction with topoisomerase II alpha and (2) the formation of tissue damaging reactive oxygen species following redox cycling of an anthracycline Fe(2+) complex. Dexrazoxane could minimise skin damage via both mechanisms, as it stops the catalytic activity of topoisomerase II alpha and thereby prevents access of anthracycline to the enzyme and thus cytotoxicity, and also acts as a strong iron chelator following opening of its two bisdioxopiperazine rings. Using the model of extravasation in a dexrazoxane-resistant transgenic mouse with a heterozygous mutation in the topoisomerase II alpha gene (Top2a(Y165S/+)), we found that dexrazoxane provided a protection against anthracycline-induced skin wounds that was indistinguishable from that found in wildtype mice. Thus, interaction with topoisomerase II alpha is not central in the pathogenesis of anthracycline-induced skin damage. In contrast to dexrazoxane, the iron-chelating bisdioxopiperazine ICRF-161 do not inhibit the catalytic cycle of topoisomerase II alpha. This compound was used to isolate and test the importance of iron in the wound pathogenesis. ICRF-161 was found ineffective in the treatment of anthracycline-induced skin damage, suggesting that iron does not play a dominant role in the genesis of wounds.
双二氧哌嗪拓扑异构酶 II 催化抑制剂右雷佐生已成功应用于临床，作为蒽环类药物外渗的解毒剂，这是基于我们的小鼠临床前研究。我们对这种小鼠外渗模型的组织学进行了研究，发现与人类的发现相似：皮下组织、真皮和表皮出现大量坏死，随后出现肉芽组织隔离和愈合，以及类似于移植物抗宿主反应的过度角化和棘皮细胞，偶尔出现细胞凋亡，淋巴细胞侵犯表皮，致密真皮结缔组织愈合。我们对这种纤维化的扩展进行了量化，发现右雷佐生干预可显著减少纤维化的扩展，这与临床观察结果一致。蒽环类药物外渗细胞毒性有几种机制，我们测试了两个主要假说：（1）与拓扑异构酶 II alpha 相互作用；（2）蒽环类药物 Fe(2+) 复合物的氧化还原循环形成组织损伤性活性氧。右雷佐生可以通过两种机制来减轻皮肤损伤，因为它可以阻止拓扑异构酶 II alpha 的催化活性，从而阻止蒽环类药物与酶的接触，从而防止细胞毒性，并且在其两个双二氧哌嗪环打开后，它还可以作为一种强大的铁螯合剂。使用拓扑异构酶 II alpha 基因杂合突变（Top2a(Y165S/+）的外渗抗性转基因小鼠模型，我们发现右雷佐生对蒽环类药物诱导的皮肤伤口提供了与野生型小鼠相同的保护作用。因此，与拓扑异构酶 II alpha 的相互作用并不是蒽环类药物诱导皮肤损伤发病机制的核心。与右雷佐生不同，铁螯合剂双二氧哌嗪 ICRF-161 不会抑制拓扑异构酶 II alpha 的催化循环。该化合物用于分离和测试铁在伤口发病机制中的重要性。我们发现 ICRF-161 对蒽环类药物诱导的皮肤损伤无效，这表明铁在伤口形成中没有起主导作用。
