De Graff William G, Myers L S, Mitchell James B, Hahn Stephen M
Radiation Biology Branch, National Cancer Institute/NIH, Building 10, Room B3-B69, 10 Center Drive, Bethesda, MD 20892, USA.
Int J Oncol. 2003 Jul;23(1):159-63.
The mechanism of Adriamycin (ADR) induced cytotoxicity is not completely understood. While a variety of mechanisms have been proposed, the production of free radicals by redox cycling of the semiquinone has been implicated in cytotoxicity, specifically for cardiotoxicity. To determine whether a scavenger of free radicals would modify the cytotoxicity of ADR, the benzoic acid derivative 3,4-dihydroxybenzoic acid (DHB) was investigated for its ability to protect against ADR-induced cytotoxicity and DNA double strand breaks in Chinese hamster V79 cells. V79 cells were treated with ADR, or its non-redox cycling analog iminodaunomycin, in the presence or absence of DHB. DHB provided significant protection (dose-modifying factor greater than 2.5 for ADR, and nearly 2 for iminodaunomycin) and also caused a dose-dependent decrease in DNA double strand breaks as measured by pulsed field gel electrophoresis. Assays of topoisomerase II activity showed that DHB inhibited topoisomerase II in a concentration-dependent manner, but did not inhibit topoisomerase I. Another non-toxic topoisomerase II inhibitor, the radioprotector WR-1065, also protected against ADR-induced cytotoxicity. These data identify DHB as a non-toxic inhibitor of DNA topoisomerase II and suggest that much of the cytotoxicity of ADR in actively growing V79 cells is due to mechanisms other than redox cycling by the semiquinone.
阿霉素（ADR）诱导细胞毒性的机制尚未完全明确。虽然已经提出了多种机制，但半醌的氧化还原循环产生自由基被认为与细胞毒性有关，尤其是心脏毒性。为了确定自由基清除剂是否会改变ADR的细胞毒性，研究了苯甲酸衍生物3,4-二羟基苯甲酸（DHB）对中国仓鼠V79细胞中ADR诱导的细胞毒性和DNA双链断裂的保护能力。V79细胞在有或没有DHB的情况下用ADR或其非氧化还原循环类似物亚氨基柔红霉素处理。DHB提供了显著的保护作用（ADR的剂量修正因子大于2.5，亚氨基柔红霉素接近2），并且通过脉冲场凝胶电泳测量，还导致DNA双链断裂呈剂量依赖性减少。拓扑异构酶II活性测定表明，DHB以浓度依赖性方式抑制拓扑异构酶II，但不抑制拓扑异构酶I。另一种无毒的拓扑异构酶II抑制剂，辐射防护剂WR-1065，也能保护细胞免受ADR诱导的细胞毒性。这些数据表明DHB是一种无毒的DNA拓扑异构酶II抑制剂，并表明在活跃生长的V79细胞中，ADR的许多细胞毒性是由半醌氧化还原循环以外的机制引起的。
