Gianni L, Viganò L, Lanzi C, Niggeler M, Malatesta V
Laboratory of Clinical Pharmacology, Istituto Nazionale Tumori, Milan, Italy.
J Natl Cancer Inst. 1988 Sep 21;80(14):1104-11. doi: 10.1093/jnci/80.14.1104.
Doxorubicin (Adr), daunorubicin (Dnr), and analogs of Adr modified in daunosamine (4'-epi-Adr and 3'-N-acetyl-Adr) were investigated with respect to their reaction with Fe(III) and analyzed for the ability of the corresponding iron complexes to sustain lipid peroxidation of isolated human platelet membranes. When the proportion of iron [25 microM Fe(III)] to Adr was 1:4, almost 50% of the metal was reduced following 1 hour of anaerobic reaction, while only approximately equal to 14% of the bound iron could be extracted as Fe(II) in the reactions of the Dnr complexes. The reaction of Adr was associated with formation of two main novel anthracyclines. One of the products had lost the C14 atom of the C9 chain and displayed chromatographic features and visible UV light spectra identical to those of authentic 9-dehydroxyacetyl-9-carboxyl-Adr. In complexes of iron and Dnr, no significant anthracycline degradation was observed. Reduction of anthracycline-bound Fe(III) by 4'-epi-Adr (38%) and 3'-N-acetyl-Adr (21.2%) was consistently less than that by Adr. Complexes of the anthracyclines investigated had different abilities to sustain lipid peroxidation, which was blocked (a) by the iron chelators deferoxamine and bathophenanthroline, indicating that Fe(III) and Fe(II) were needed for the reaction, and (b) by ICRF-198, the chelating product that forms intracellularly by hydrolysis of razoxane, which can prevent Adr cardiotoxicity. Peroxidation was not affected by scavengers of reduced oxygen radicals (superoxide dismutase, catalase, and mannitol). The isolated membranes contributed to the reduction of anthracycline-bound Fe(III) and probably represented the main determinant of lipid peroxidation by iron-Dnr. Lipid peroxidation was significantly less for complexes of iron with 4'-epi-Adr or 3'-N-acetyl-Adr than for complexes of iron with Adr. The observed differences may be relevant to the different biologic properties of Adr and its analogs, in particular their different degrees of cardiotoxicity.
研究了阿霉素（Adr）、柔红霉素（Dnr）以及柔红糖胺修饰的阿霉素类似物（4'-表阿霉素和3'-N-乙酰阿霉素）与Fe(III)的反应，并分析了相应铁络合物引发人血小板膜脂质过氧化的能力。当铁[25 microM Fe(III)]与Adr的比例为1:4时，厌氧反应1小时后，近50%的金属被还原，而在Dnr络合物的反应中，只有约14%的结合铁能以Fe(II)形式被提取出来。Adr的反应伴随着两种主要新型蒽环类化合物的形成。其中一种产物失去了C9链的C14原子，其色谱特征和可见紫外光谱与正品9-脱氢乙酰基-9-羧基-Adr相同。在铁与Dnr的络合物中，未观察到明显的蒽环类化合物降解。4'-表阿霉素（38%）和3'-N-乙酰阿霉素（21.2%）对蒽环类化合物结合的Fe(III)的还原作用始终低于Adr。所研究的蒽环类化合物络合物引发脂质过氧化的能力不同，铁螯合剂去铁胺和邻二氮菲可阻断这种过氧化反应，这表明该反应需要Fe(III)和Fe(II)参与；雷佐生水解后在细胞内形成的螯合产物ICRF-198也可阻断这种过氧化反应，雷佐生可预防Adr的心脏毒性。过氧化反应不受氧自由基清除剂（超氧化物歧化酶、过氧化氢酶和甘露醇）的影响。分离出的膜有助于还原蒽环类化合物结合的Fe(III)，可能是铁-Dnr引发脂质过氧化的主要决定因素。铁与4'-表阿霉素或3'-N-乙酰阿霉素形成的络合物引发的脂质过氧化明显低于铁与Adr形成的络合物。观察到的差异可能与Adr及其类似物的不同生物学特性有关，尤其是它们不同程度的心脏毒性。
