Sehested M, Jensen P B, Sørensen B S, Holm B, Friche E, Demant E J
Department of Pathology, Sundby Hospital, Copenhagen, Denmark.
Biochem Pharmacol. 1993 Aug 3;46(3):389-93. doi: 10.1016/0006-2952(93)90514-w.
The effect of the bisdioxopiperazine cardioprotector ICRF-187 (ADR-529, dexrazoxan) on drug-induced DNA damage and cytotoxicity was studied. Using alkaline elution assays, ICRF-187 in a dose-dependent manner inhibited the formation of DNA single strand breaks (SSBs) as well as DNA-protein cross-links induced by drugs such as VP-16 (etoposide), m-AMSA [4'-(9-acridinylamino)-methanesulfon-m-anisidide], daunorubicin and doxorubicin (Adriamycin) which are known to stimulate DNA-topoisomerase II cleavable complex formation. Thus, 50% inhibition of DNA SSBs induced by 5 microM doxorubicin occurred already at equimolar ICRF-187. In contrast, ICRF-187 did not affect DNA SSBs induced by H2O2. In clonogenic assay, ICRF-187 in non-toxic doses antagonized both VP-16 and daunorubicin cytotoxicity in a dose-dependent manner. Our results indicate that the previously described acute in vivo protection by ICRF-187 against anthracycline toxicity may be due to inhibition of topoisomerase II activity. The antagonistic effect of ICRF-187 on daunorubicin cytotoxicity should be taken into consideration when planning clinical trials.
研究了双二氧哌嗪类心脏保护剂ICRF - 187（ADR - 529，右丙亚胺）对药物诱导的DNA损伤和细胞毒性的影响。使用碱性洗脱分析方法，ICRF - 187以剂量依赖方式抑制了DNA单链断裂（SSB）的形成以及由VP - 16（依托泊苷）、m - AMSA [4' -（9 - 吖啶基氨基）-甲磺酰间茴香胺]、柔红霉素和阿霉素（阿霉素）等药物诱导的DNA - 蛋白质交联，这些药物已知会刺激DNA拓扑异构酶II可裂解复合物的形成。因此，在等摩尔的ICRF - 187存在时，5 microM阿霉素诱导的DNA SSB已有50%被抑制。相比之下，ICRF - 187不影响H2O2诱导的DNA SSB。在克隆形成试验中，无毒剂量的ICRF - 187以剂量依赖方式拮抗了VP - 16和柔红霉素的细胞毒性。我们的结果表明，先前描述的ICRF - 187在体内对蒽环类药物毒性的急性保护作用可能是由于其对拓扑异构酶II活性的抑制。在规划临床试验时，应考虑ICRF - 187对柔红霉素细胞毒性的拮抗作用。
