Hasinoff B B
Faculty of Pharmacy, University of Manitoba Winnipeg, Canada.
Free Radic Res. 1995 Apr;22(4):319-25. doi: 10.3109/10715769509145644.
ICRF-187 (dexrazoxane) is currently in clinical trials as a cardioprotective agent for the prevention of doxorubicin-induced cardiotoxicity. ICRF-187 likely acts through its strongly metal ion-binding rings-opened hydrolysis product ADR-925 by removing iron from its complex with doxorubicin or by chelating free iron. The ability of NADPH-cytochrome-P450 reductase to promote hydroxyl radical formation by iron complexes of ADR-925 and EDTA was compared by EPR spin trapping. The iron-EDTA complex produced hydroxyl radicals at six times the rate that the iron-ADR-925 complex did. The aerobic oxidation of ferrous complexes of ADR-925, its tetraacid analog, EDTA and DTPA was followed spectrophotometrically. The iron(II)-ADR-925 complex was aerobically oxidized 700 times slower than was the EDTA complex. It is concluded that even though ADR-925 does not completely eliminate iron-based hydroxyl radical production, it likely protects by preventing site-specific hydroxyl radical damage by the iron-doxorubicin complex.
ICRF - 187（右丙亚胺）目前正处于临床试验阶段，作为一种心脏保护剂用于预防阿霉素诱导的心脏毒性。ICRF - 187可能通过其强金属离子结合的开环水解产物ADR - 925发挥作用，该产物通过从与阿霉素的复合物中去除铁或螯合游离铁来实现。通过电子顺磁共振（EPR）自旋捕获比较了NADPH - 细胞色素 - P450还原酶促进ADR - 925和EDTA的铁络合物形成羟基自由基的能力。铁 - EDTA络合物产生羟基自由基的速率是铁 - ADR - 925络合物的六倍。用分光光度法跟踪了ADR - 925及其四酸类似物、EDTA和DTPA的亚铁络合物的有氧氧化过程。铁（II）- ADR - 925络合物的有氧氧化速度比EDTA络合物慢700倍。得出的结论是，尽管ADR - 925不能完全消除基于铁的羟基自由基的产生，但它可能通过防止铁 - 阿霉素络合物造成的位点特异性羟基自由基损伤来起到保护作用。
