Evaluation of the topoisomerase II-inactive bisdioxopiperazine ICRF-161 as a protectant against doxorubicin-induced cardiomyopathy.
Anthracycline-induced cardiomyopathy is a major problem in anti-cancer therapy. The only approved agent for alleviating this serious dose limiting side effect is ICRF-187 (dexrazoxane). The current thinking is that the ring-opened hydrolysis product of this agent, ADR-925, which is formed inside cardiomyocytes, removes iron from its complexes with anthracyclines, hereby reducing the concentration of highly toxic iron-anthracycline complexes that damage cardiomyocytes by semiquinone redox recycling and the production of free radicals. However, the 2 carbon linker ICRF-187 is also is a catalytic inhibitor of topoisomerase II, resulting in the risk of additional myelosuppression in patients receiving ICRF-187 as a cardioprotectant in combination with doxorubicin. The development of a topoisomerase II-inactive iron chelating compound thus appeared attractive. In the present paper we evaluate the topoisomerase II-inactive 3 carbon linker bisdioxopiperazine analog ICRF-161 as a cardioprotectant. We demonstrate that this compound does chelate iron and protects against doxorubicin-induced LDH release from primary rat cardiomyocytes in vitro, similarly to ICRF-187. The compound does not target topoisomerase II in vitro or in cells, it is well tolerated and shows similar exposure to ICRF-187 in rodents, and it does not induce myelosuppression when given at high doses to mice as opposed to ICRF-187. However, when tested in a model of chronic anthracycline-induced cardiomyopathy in spontaneously hypertensive rats, ICRF-161 was not capable of protecting against the cardiotoxic effects of doxorubicin. Modulation of the activity of the beta isoform of the topoisomerase II enzyme by ICRF-187 has recently been proposed as the mechanism behind its cardioprotection. This concept is thus supported by the present study in that iron chelation alone does not appear to be sufficient for protection against anthracycline-induced cardiomyopathy.
Martin
Elke
E
TopoTarget A/S, Symbion Science Park, Fruebjergvej 3, Copenhagen 2100, Denmark.
Thougaard
Annemette Vinding
AV
Grauslund
Morten
M
Jensen
Peter B
PB
Bjorkling
Fredrik
F
Hasinoff
Brian B
BB
Tjørnelund
Jette
J
Sehested
Maxwell
M
Jensen
Lars H
LH
D000818:Animals; D000831:Animals, Newborn; D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D003114:Colony-Forming Units Assay; D016831:Crithidia fasciculata / Q000378:metabolism; D004247:DNA / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D005290:Ferric Compounds / Q000494:pharmacology; D053208:Kaplan-Meier Estimate; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D008929:Mitochondria, Heart / Q000187:drug effects; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology; D051381:Rats; D011918:Rats, Inbred SHR; D011929:Razoxane / Q000493:pharmacokinetics / Q000494:pharmacology*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000473:pathology; D019210:Troponin I / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D005290:Ferric Compounds; D019210:Troponin I; D011929:Razoxane; D004317:Doxorubicin; D004247:DNA; D007770:L-Lactate Dehydrogenase; D004250:DNA Topoisomerases, Type II