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)

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Survival / drug effects
  • DNA Damage
  • DNA Topoisomerases, Type II / metabolism
  • DNA, Single-Stranded
  • Daunorubicin / antagonists & inhibitors
  • Daunorubicin / pharmacology*
  • Drug Interactions
  • Etoposide / pharmacology*
  • Humans
  • Razoxane / pharmacology*
  • Tumor Cells, Cultured / drug effects


  • DNA, Single-Stranded
  • Razoxane
  • Etoposide
  • DNA Topoisomerases, Type II
  • Daunorubicin