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).
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.
Department of Pathology, Sundby Hospital, Copenhagen, Denmark.
M
M
Sehested
P B
PB
Jensen
B S
BS
Sørensen
B
B
Holm
E
E
Friche
E J
EJ
Demant
D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004277:DNA, Single-Stranded; D003630:Daunorubicin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D011929:Razoxane / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D004277:DNA, Single-Stranded; D011929:Razoxane; D005047:Etoposide; D004250:DNA Topoisomerases, Type II; D003630:Daunorubicin