Antagonistic effect of the cardioprotector (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane (ICRF-187) on DNA breaks and cytotoxicity induced by the topoisomerase II directed drugs daunorubicin and etoposide (VP-16).
Antagonistic effect of the cardioprotector (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane (ICRF-187) on DNA breaks and cytotoxicity induced by the topoisomerase II directed drugs daunorubicin and etoposide (VP-16).
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心脏保护剂 ( )-1,2-双(3,5-二氧代哌嗪基-1-基)丙烷 (ICRF-187) 对拓扑异构酶 II 导向药物柔红霉素和依托泊苷 (VP-16) 诱导的 DNA 断裂和细胞毒性的拮抗作用
DOI：
10.1016/0006-2952(93)90514-w
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发表时间：
1993
影响因子：
5.8
通讯作者：
Erland J. F. Demant
中科院分区：
文献类型：
--
作者：
M. Sehested;P. B. Jensen;Boe Sandahl Sorensen;Bente Holm;E. Friche;Erland J. F. Demant
研究了双二氧代哌嗪心脏保护剂ICRF-187（ADR-529，dexrazoxan）对药物诱导的DNA损伤和细胞毒性的影响。使用碱性洗脱试验，ICRF-187以剂量依赖性方式抑制由VP-16（依托泊苷）、m-AMSA [4′-（9-吖啶氨基）-甲磺酰-间-茴香胺]、柔红霉素和阿霉素（Adriamycin®）等药物诱导的DNA单链断裂（SSB）以及DNA-蛋白质交联的形成，这些药物已知可刺激DNA-拓扑异构酶II可切割复合物的形成。因此，在等摩尔ICRF-187时，5 μM多柔比星诱导的DNA SSB抑制率已达到50%。相反，ICRF-187不影响H2 O2诱导的DNA SSB。在克隆形成试验中，无毒剂量的ICRF-187以剂量依赖的方式拮抗VP-16和柔红霉素的细胞毒性。我们的研究结果表明，先前描述的急性体内保护ICRF-187对蒽环类药物的毒性可能是由于抑制拓扑异构酶II的活性。ICRF-187对柔红霉素细胞毒性的拮抗作用应在计划临床试验时予以考虑。
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 μM 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 acutein vivoprotection 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.
影响因子：
56.9
作者：
TEWEY, KM;ROWE, TC;LIU, LF
通讯作者：
LIU, LF