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)

doi:10.1016/0006-2952(93)90514-W

Biochemical Pharmacology

Volume 46, Issue 3, 3 August 1993, Pages 389-393

https://doi.org/10.1016/0006-2952(93)90514-W Get rights and content

Abstract

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 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.

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Citation Excerpt :
The anticancer activity of DOX relates to its direct DNA damage if causes or to interference with DNA repair [3]; whereas the mechanisms of DOX-induced cardiotoxicity are attributed, at least in part, to the generation of reactive oxygen species (ROS), mitochondrial damage, impaired calcium homeostasis and induction of cell apoptosis [1,4,5]. Dexrazoxane is the only agent licensed by European Medicines Agency and the US Food and Drug Administration for reducing the cardiotoxicity induced by DOX, but it may interfere with the anticancer activity of anthracycline antibiotics and also potentiates the myelosuppressive effects of DOX [6–9]. Melatonin (N-acetyl-5-methoxytryptamine), an endogenously-produced indolamine, is a known potent antioxidant and exerts myocardial protection against various cardiovascular diseases (e.g., ischemia/reperfusion injury, diabetic cardiomyopathy, myocardial hypertrophy) [10,11].
Doxorubicin (DOX) is a highly effective anticancer anthracycline drug, but its side effects at the level of the heart has limited its widespread clinical application. Melatonin is a documented potent antioxidant, nontoxic and cardioprotective agent, and it is involved in maintaining mitochondrial homeostasis and function. The present study established acute DOX-induced cardiotoxicity models in both H9c2 cells incubated with 1 μM DOX and C57BL/6 mice treated with DOX (20 mg/kg cumulative dose). Melatonin markedly alleviated the DOX-induced acute cardiac dysfunction and myocardial injury. Both in vivo and in vitro studies verified that melatonin inhibited DOX-induced mitochondrial dysfunction and morphological disorders, apoptosis, and oxidative stress via the activation of AMPK and upregulation of PGC1α with its downstream signaling (NRF1, TFAM and UCP2). These effects were reversed by the use of AMPK siRNA or PGC1α siRNA in H9c2 cells, and were also negated by the cotreatment with AMPK inhibitor Compound C in vivo. Moreover, PGC1α knockdown was without effect on the AMPK phosphorylation induced by melatonin in the DOX treated H9c2 cells. Therefore, AMPK/PGC1α pathway activation may represent a new mechanism for melatonin exerted protection against acute DOX cardiotoxicity through preservation of mitochondrial homeostasis and alleviation of oxidative stress and apoptosis.
Dexrazoxane for cardioprotection in older adults with acute myeloid leukemia
2017, Leukemia Research Reports
Citation Excerpt :
Although the cardioprotective benefits of dexrazoxane have been clearly demonstrated in both pediatric (mostly hematologic malignancies) and adult (mostly breast cancer) patients, this agent is not currently approved for AML patients receiving anthracycline therapy. One concern was the possibility of dexrazoxane decreasing chemotherapeutic efficacy based on preclinical data showing that dexrazoxane can antagonize the cytotoxicity induced by topoisomerase II directed drugs, daunorubicin and etoposide, in AML cells [14]. More recent reports have shown that dexrazoxane itself may exert anti-leukemic effects.
Anthracyclines constitute the backbone of intensive adult acute myeloid leukemia (AML) therapy. Cardiotoxicity is one of its most serious adverse effects, and its incidence increases with cumulative dose. Dexrazoxane is a cardioprotective agent used in conjunction with anthracycline therapy. There is limited data of its usage in adult AML patients. We report the outcomes of six older adults at high risk of anthracycline-induced cardiotoxicity who received dexrazoxane during induction/re-induction therapy. Five had preserved left-ventricular function while two proceeded onto stem-cell transplantation. Additional investigation of dexrazoxane in adult leukemia therapy is warranted, particularly in older patients at highest risk for cardiovascular mortality.
Effects of mndpdp and icrf-187 on doxorubicin-induced cardiotoxicity and anticancer activity
2012, Translational Oncology
Oxidative stress participates in doxorubicin (Dx)-induced cardiotoxicity. The metal complex MnDPDP and its metabolite MnPLED possess SOD-mimetic activity, DPDP and PLED have, in addition, high affinity for iron. Mice were injected intravenously with MnDPDP, DPDP, or dexrazoxane (ICRF-187). Thirty minutes later, mice were killed, the left atria were hung in organ baths and electrically stimulated, saline or Dx was added, and the contractility was measured for 60 minutes. In parallel experiments, 10 µM MnDPDP or MnPLED was added directly into the organ bath. The effect of MnDPDP on antitumor activity of Dx against two human tumor xenografts (MX-1 and A2780) was investigated. The in vitro cytotoxic activity was studied by co-incubating A2780 cells with MnDPDP, DPDP, and/or Dx. Dx caused a marked reduction in contractile force. In vivo treatment with MnDPDP and ICRF-187 attenuated the negative effect of Dx. When added directly into the bath, MnDPDP did not protect, whereas MnPLED attenuated the Dx effect by approximately 50%. MnDPDP or ICRF-187 did not interfere negatively with the anti-tumor activity of Dx, either in vivo or in vitro. Micromolar concentrations of DPDP but not MnDPDP displayed an in vitro cytotoxic activity against A2780 cells. The present results show that MnDPDP, after being metabolized to MnPLED, protects against acute Dx cardiotoxicity. Both in vivo and in vitro experiments show that cardioprotection takes place without interfering negatively with the anticancer activity of Dx. Furthermore, the results suggest that the previously described cytotoxic in vivo activity of MnDPDP is an inherent property of DPDP.
A murine experimental anthracycline extravasation model: Pathology and study of the involvement of topoisomerase II alpha and iron in the mechanism of tissue damage
2010, Toxicology
Citation Excerpt :
Anthracyclines are believed to exert their anti-tumour activity by acting as so-called topoisomerase II poisons, that is, they stabilize the topoisomerase II–DNA cleavable complex, which in turn leads to the formation of lethal DNA double strand breaks. Based on the ability of dexrazoxane to be a highly specific and potent catalytic inhibitor of topoisomerase II, and as such abrogating the effect of topoisomerase II poisons (Sehested et al., 1993), and on a possible tissue-rescuing effect via its iron chelating effect, we proposed that dexrazoxane could be an effective antidote for anthracycline extravasation and studied this using a mouse model of extravasation. Dexrazoxane was shown to prevent skin necrosis following a subcutaneous injection of daunorubicin, doxorubicin, epirubicin or idarubicin (Langer et al., 2000).
The bisdioxopiperazine topoisomerase II catalytic inhibitor dexrazoxane has successfully been introduced into the clinic as an antidote to accidental anthracycline extravasation based on our preclinical mouse studies. The histology of this mouse extravasation model was investigated and found to be similar to findings in humans: massive necrosis in the subcutis, dermis and epidermis followed by sequestration and healing with granulation tissue, and a graft-versus-host-like reaction with hyperkeratotic and acanthotic keratinocytes, occasional apoptoses, epidermal invasion by lymphocytes and healing with dense dermal connective tissue. The extension of this fibrosis was quantified, and dexrazoxane intervention resulted in a statistically significant decrease in fibrosis extension, as also observed in the clinic. Several mechanisms have been proposed in anthracycline extravasation cytotoxicity, and we tested two major hypotheses: (1) interaction with topoisomerase II alpha and (2) the formation of tissue damaging reactive oxygen species following redox cycling of an anthracycline Fe²⁺ complex. Dexrazoxane could minimise skin damage via both mechanisms, as it stops the catalytic activity of topoisomerase II alpha and thereby prevents access of anthracycline to the enzyme and thus cytotoxicity, and also acts as a strong iron chelator following opening of its two bisdioxopiperazine rings. Using the model of extravasation in a dexrazoxane-resistant transgenic mouse with a heterozygous mutation in the topoisomerase II alpha gene (Top2a^Y165S/+), we found that dexrazoxane provided a protection against anthracycline-induced skin wounds that was indistinguishable from that found in wildtype mice. Thus, interaction with topoisomerase II alpha is not central in the pathogenesis of anthracycline-induced skin damage. In contrast to dexrazoxane, the iron-chelating bisdioxopiperazine ICRF-161 do not inhibit the catalytic cycle of topoisomerase II alpha. This compound was used to isolate and test the importance of iron in the wound pathogenesis. ICRF-161 was found ineffective in the treatment of anthracycline-induced skin damage, suggesting that iron does not play a dominant role in the genesis of wounds.
Chloroquine and its analogs: A new promise of an old drug for effective and safe cancer therapies
2009, European Journal of Pharmacology
Chloroquine (CQ), N′-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-1,4-diamine, is widely used as an effective and safe anti-malarial and anti-rheumatoid agent. CQ was discovered 1934 as “Resochin” by Andersag and co-workers at the Bayer laboratories. Ironically, CQ was initially ignored for a decade because it was considered too toxic to use in humans. CQ was “re-discovered” during World War II in the United States in the course of anti-malarial drug development. The US government-sponsored clinical trials during this period showed unequivocally that CQ has a significant therapeutic value as an anti-malarial drug. Consequently, CQ was introduced into clinical practice in 1947 for the prophylaxis treatment of malaria (Plasmodium vivax, ovale and malariae). CQ still remains the drug of choice for malaria chemotherapy because it is highly effective and well tolerated by humans. In addition, CQ is widely used as an anti-inflammatory agent for the treatment of rheumatoid arthritis, lupus erythematosus and amoebic hepatitis. More recently, CQ has been studied for its potential as an enhancing agent in cancer therapies. Accumulating lines of evidence now suggest that CQ can effectively sensitize cell-killing effects by ionizing radiation and chemotherapeutic agents in a cancer-specific manner. The lysosomotrophic property of CQ appears to be important for the increase in efficacy and specificity. Although more studies are needed, CQ may be one of the most effective and safe sensitizers for cancer therapies. Taken together, it appears that the efficacy of conventional cancer therapies can be dramatically enhanced if used in combination with CQ and its analogs.
Evaluation of the topoisomerase II-inactive bisdioxopiperazine ICRF-161 as a protectant against doxorubicin-induced cardiomyopathy
2009, Toxicology
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.

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Biochemical Pharmacology

Abstract

References (24)

Evidence of the selective alteration of anthracycline activity due to modulation by ICRF-187 (ADR-529)

Pharmacol Ther

Biological properties of ICRF-159 and related bis(dioxopiperazine) compounds

Adv Pharmacol Chemother

Carrier-mediated transport of daunorubicin, adriamycin, and rubidazone in Ehrlich ascites tumour cells

Biochem Pharmacol

H₂O₂ as a DNA fragmenting agent in the alkaline elution interstrand crosslinking and DNA-protein crosslinking assays

Anal Biochem

Iron is the intracellular metal involved in the production of DNA damage by oxygen radicals

Mutat Res

Lethal and sublethal effects of the combination of doxorubicin and the bisdioxopiperazine, (+)-1,2-bis(3–5-dioxo-piperazinyl-1-yl)propane (ICRF-187), on murine sarcoma S180 in vitro

Biochem Pharmacol

Mode of action of topoisomerase II-targeting agents at a specific DNA sequence: uncoupling the DNA binding, cleavage and religation events

J Mol Biol

Inhibition of type II topoisomerase by fostriecin

Biochem Pharmacol

ICRF-187 permits longer treatment with doxorubicin in woman with breast cancer

J Clin Oncol

Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II

Science

DNA topoisomerase poisons as antitumor drugs

Annu. Rev Biochem

Inhibition of topoisomerase II by antitumor agents bis(2,6-dioxopiperazine) derivatives

Cancer Res

Cited by (99)

AMPK/PGC1α activation by melatonin attenuates acute doxorubicin cardiotoxicity via alleviating mitochondrial oxidative damage and apoptosis

Dexrazoxane for cardioprotection in older adults with acute myeloid leukemia

Effects of mndpdp and icrf-187 on doxorubicin-induced cardiotoxicity and anticancer activity

A murine experimental anthracycline extravasation model: Pathology and study of the involvement of topoisomerase II alpha and iron in the mechanism of tissue damage

Chloroquine and its analogs: A new promise of an old drug for effective and safe cancer therapies

Evaluation of the topoisomerase II-inactive bisdioxopiperazine ICRF-161 as a protectant against doxorubicin-induced cardiomyopathy