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Brian B Hasinoff - One of the best experts on this subject based on the ideXlab platform.
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The Role of Topoisomerase IIβ in the Mechanisms of Action of the Doxorubicin Cardioprotective Agent Dexrazoxane
Cardiovascular toxicology, 2019Co-Authors: Brian B Hasinoff, Daywin PatelAbstract:Dexrazoxane is clinically used to reduce doxorubicin cardiotoxicity and anthracycline-induced extravasation injury. Dexrazoxane is a strong catalytic inhibitor of topoisomerase II. It can also undergo metabolism to form an iron-binding analog of EDTA. Dexrazoxane was originally thought to act by reducing iron-dependent doxorubicin-based oxidative stress. However, a competing hypothesis posits that Dexrazoxane may be protective through its ability to inhibit and reduce topoisomerase IIβ protein levels in the heart. A primary neonatal rat myocyte model was used to study the mechanism by which Dexrazoxane protects against doxorubicin-induced myocyte damage. This study characterized the kinetics of the rapid and nearly complete Dexrazoxane-induced loss of topoisomerase IIβ protein from neonatal rat cardiac myocytes. Immunofluorescent staining of attached myocytes for topoisomerase IIβ revealed that most of the topoisomerase IIβ was localized to the nucleus, although it was also present in the cytoplasm. Dexrazoxane treatment resulted in an almost complete reduction of topoisomerase IIβ in the nucleus and a lesser reduction in the cytoplasm. The recovery of topoisomerase IIβ levels after a pulse topoisomerase IIβ inhibitory concentration of Dexrazoxane occurred slowly, with partial recovery only occurring after 24 h. The ability of Dexrazoxane to reduce doxorubicin-induced damage to myocytes was greatest when topoisomerase IIβ levels were at their lowest.
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A review of the preclinical development of Dexrazoxane
Progress in Pediatric Cardiology, 2014Co-Authors: Eugene H Herman, Brian B Hasinoff, Rudolf Steiner, Steven E. LipshultzAbstract:Abstract We review here the experiments by which Dexrazoxane was identified as a protectant against two serious anthracycline toxicities: cardiotoxicity and accidental extravasation injury. These experiments led to the successful use of Dexrazoxane as a cardioprotectant in clinical cancer trials. Several preclinical studies established that Dexrazoxane reduced cardiotoxicity without altering the anti-neoplastic activity of doxorubicin and its analogs and without increasing non-cardiac tissue toxicity. In animal models, Dexrazoxane has also reduced the toxicity of several other substances, including alloxan, acetaminophen, bleomycin, and oxygen. Experimental models have further led to the use of serum biomarkers to detect and monitor subclinical cardiotoxicity in children and adults with cancer. Studies of the chemistry, biochemistry, metabolism, pharmacokinetics and pharmacodynamics of Dexrazoxane have so far revealed two important cytoprotective activities: it is rapidly metabolized to an active iron chelation form (ADR-925), which prevents oxidative stress on cardiac tissue, and it may be cytoprotective by inhibiting topoisomerase IIβ. The animal models described here suggest a potential clinical use for Dexrazoxane in reducing anthracycline-mediated cardiotoxicity when given before each anthracycline dose and in preventing accidental anthracycline extravasation. Dexrazoxane is currently licensed to treat these two serious conditions.
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Dexrazoxane: how it works in cardiac and tumor cells. Is it a prodrug or is it a drug?
Cardiovascular toxicology, 2007Co-Authors: Brian B Hasinoff, Eugene H HermanAbstract:Dexrazoxane is highly effective in reducing anthracycline-induced cardiotoxicity and extravasation injury and is used clinically for these indications. Dexrazoxane has two biological activities: it is a prodrug that is hydrolyzed to an iron chelating EDTA-type structure and it is also a strong inhibitor of topoisomerase II. Doxorubicin is able to be reductively activated to produce damaging reactive oxygen species. Iron-dependent cellular damage is thought to be responsible for its cardiotoxicity. The available experimental evidence supports the conclusion that Dexrazoxane reduces doxorubicin cardiotoxicity by binding free iron and preventing site-specific oxidative stress on cardiac tissue. However, it cannot be ruled out that Dexrazoxane may also be protective through its ability to inhibit topoisomerase II.
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Metabolism of the cardioprotective drug Dexrazoxane and one of its metabolites by isolated rat myocytes, hepatocytes, and blood.
Drug metabolism and disposition: the biological fate of chemicals, 2005Co-Authors: Patricia E. Schroeder, Guqi Wang, Frank J. Burczynski, Brian B HasinoffAbstract:The metabolism of the antioxidant cardioprotective agent Dexrazoxane (ICRF-187) and one of its one-ring open metabolites to its active metal ion binding form N,N'-[(1S)-1-methyl-1,2-ethanediyl-]bis[(N-(2-amino-2-oxoethyl)]glycine (ADR-925) has been investigated in neonatal rat myocyte and adult rat hepatocyte suspensions, and in human and rat blood and plasma with a view to characterizing their hydrolysis-activation. Dexrazoxane is clinically used to reduce the iron-based oxygen free radical-mediated cardiotoxicity of the anticancer drug doxorubicin. Dexrazoxane may act through its hydrolysis product ADR-925 by removing iron from the iron-doxorubicin complex, or binding free iron, thus preventing oxygen radical formation. Our results indicate that Dexrazoxane underwent partial uptake and/or hydrolysis by myocytes. A one-ring open metabolite of Dexrazoxane underwent nearly complete dihydroorotase-catalyzed metabolism in a myocyte suspension. Hepatocytes that contain both dihydropyrimidinase and dihydroorotase completely hydrolyzed Dexrazoxane to ADR-925 and released it into the extracellular medium. Thus, in hepatocytes, the two liver enzymes acted in concert, and sequentially, on Dexrazoxane, first to produce the two ring-opened metabolites, and then to produce the metabolite ADR-925. We also showed that the hydrolysis of one of these metabolites was promoted by Ca2+ and Mg2+ in plasma, and thus, further metabolism of these intermediates likely occurs in the plasma after they are released from the liver and kidney. In conclusion, these studies provide a nearly complete description of the metabolism of Dexrazoxane by myocytes and hepatocytes to its presumably active form, ADR-925.
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Synthesis and characterization of the biological activity of the cisplatin analogs cis-PtCl2(Dexrazoxane) and cis-PtCl2(levrazoxane) of the topoisomerase II inhibitors Dexrazoxane (ICRF-187) and levrazoxane (ICRF-186).
Cancer Research, 2004Co-Authors: Brian B HasinoffAbstract:3077 The bisdioxopiperazines Dexrazoxane and levrazoxane are strong catalytic inhibitors of mammalian DNA topoisomerase II. The individual stereoisomers of their platinum(II) complexes, cis-PtCl2(Dexrazoxane) and cis-PtCl2(levrazoxane), were synthesized and their structures were determined by x-ray crystallography. Dexrazoxane and levrazoxane inhibit cell growth because they inhibit topoisomerase II, whereas cisplatin acts through the formation of DNA cross-links. It was hypothesized that platinum(II) complexes of Dexrazoxane and levrazoxane would retain both activities and yield drugs with a dual mode of action. Both cis-PtCl2(Dexrazoxane) and cis-PtCl2(levrazoxane) inhibited Chinese hamster ovary cell growth, but more weakly than Dexrazoxane and levrazoxane did. Based on the inability of these platinum complexes to inhibit the catalytic activity of topoisomerase II it was concluded that these compounds did not inhibit cell growth by. targeting topoisomerase II. The recent x-ray structure of Dexrazoxane bound to the ATPase region of a yeast topoisomerase II has been used to model the platinum complexes into the bisdioxopiperazine binding site. A comparison of the conformation of cis-PtCl2(Dexrazoxane) to that of Dexrazoxane bound to the dimer interface of topoisomerase II showed that the highly constrained cis-PtCl2(Dexrazoxane) was in a highly unfavorable conformation for binding. Also neither of the platinum complexes were able to cross-link DNA. Thus the cell growth inhibitory activity of these complexes were also not likely due to any cisplatin-type cross-linking activity. Support: CIHR and a Canada Research Chair in Drug Development.
P. Vici - One of the best experts on this subject based on the ideXlab platform.
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The current and future role of Dexrazoxane as a cardioprotectant in anthracycline treatment: expert panel review
Journal of Cancer Research and Clinical Oncology, 2004Co-Authors: S. M. Swain, P. ViciAbstract:This article summarizes the views of an expert meeting of cardiologists and oncologists on the use of Dexrazoxane in anthracycline-based chemotherapy. Anthracycline-induced cardiotoxicity remains a major concern and new trends in treatment (e.g., combination of an anthracycline with other agents) will ensure that it remains a problem. Dexrazoxane reduces this cardiotoxicity in adults and children with a range of tumor types. Further research may help to identify those patients who are at particular risk of cardiotoxicity and who would benefit the most from Dexrazoxane. There are also numerous possibilities for Dexrazoxane in other clinical situations, which must be addressed in future trials.
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The current and future role of Dexrazoxane as a cardioprotectant in anthracycline treatment: expert panel review.
Journal of cancer research and clinical oncology, 2003Co-Authors: Sandra M. Swain, P. ViciAbstract:This article summarizes the views of an expert meeting of cardiologists and oncologists on the use of Dexrazoxane in anthracycline-based chemotherapy. Anthracycline-induced cardiotoxicity remains a major concern and new trends in treatment (e.g., combination of an anthracycline with other agents) will ensure that it remains a problem. Dexrazoxane reduces this cardiotoxicity in adults and children with a range of tumor types. Further research may help to identify those patients who are at particular risk of cardiotoxicity and who would benefit the most from Dexrazoxane. There are also numerous possibilities for Dexrazoxane in other clinical situations, which must be addressed in future trials.
Sandra M. Swain - One of the best experts on this subject based on the ideXlab platform.
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The current and future role of Dexrazoxane as a cardioprotectant in anthracycline treatment: expert panel review.
Journal of cancer research and clinical oncology, 2003Co-Authors: Sandra M. Swain, P. ViciAbstract:This article summarizes the views of an expert meeting of cardiologists and oncologists on the use of Dexrazoxane in anthracycline-based chemotherapy. Anthracycline-induced cardiotoxicity remains a major concern and new trends in treatment (e.g., combination of an anthracycline with other agents) will ensure that it remains a problem. Dexrazoxane reduces this cardiotoxicity in adults and children with a range of tumor types. Further research may help to identify those patients who are at particular risk of cardiotoxicity and who would benefit the most from Dexrazoxane. There are also numerous possibilities for Dexrazoxane in other clinical situations, which must be addressed in future trials.
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Adult multicenter trials using Dexrazoxane to protect against cardiac toxicity.
Seminars in Oncology, 1998Co-Authors: Sandra M. SwainAbstract:Two large multicenter placebo controlled trials (088001 and 088006) in metastatic breast cancer found a significant cardioprotective effect of Dexrazoxane when administered with doxorubicin. A delayed dose analysis found a protective effect even after a cumulative dose of doxorubicin of 300 mg/m2. Exploratory analysis combing the arms on the two studies found a cardioprotective effect of Dexrazoxane either initially or after 300 mg/m2 when administered in patients older than 65 years, compared to patients receiving only placebo. Also, patients with an ejection fraction within 10% above the lower limit of normal were protected with Dexrazoxane. Objective response rates were borderline significantly lower for patients receiving Dexrazoxane. Recommendations are to administer Dexrazoxane after 300 mg/m2.
A Schiavetti - One of the best experts on this subject based on the ideXlab platform.
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echocardiographic long term follow up of adult survivors of pediatric cancer treated with Dexrazoxane anthracyclines association
International Journal of Cardiology, 2020Co-Authors: Domenico Filomena, Paolo Versacci, Sara Cimino, C Mattiucci, Viviana Maestrini, D Cantisani, V Petronilli, Luciano Agati, A SchiavettiAbstract:Abstract Aims Cardiovascular disease is a well-recognized cause of increased late morbidity and mortality among survivors of childhood cancer treated with anthracyclines. Co-administration of Dexrazoxane has been shown to significantly reduce short-term and mid-term cardiotoxicity. Aim of this study was to assess cardiac function in long-term (>10 years) survivors of childhood tumors treated with Dexrazoxane/anthracycline association. Methods and results Twenty cancer survivors previously treated with co-administration of anthracyclines-Dexrazoxane for childhood renal tumors or sarcoma and a control group of 20 healthy subjects were enrolled in the study. Echocardiographic measurements included 3D left ventricular (LV) ejection fraction (LVEF) and LV and right ventricular (RV) global longitudinal strain (GLS). Among cancer survivors group the median age at diagnosis was 5 years (1–17) and they were evaluated at median follow-up time of 21.5 years (10–26). No evidence of cardiac toxicity, as defined by current guidelines, was reported in all survivors. No significant differences in standard and deformation imaging parameters were observed between survivors and controls (3D LVEF 58 ± 3% vs 60 ± 5% p = NS; LV GLS −21 ± 1% vs −21 ± 2% p = NS; RV GLS −23 ± 2% vs −23 ± 5% p = NS). No second tumor was registered in Dexrazoxane-treated survivors. Conclusions Our findings may support the role of Dexrazoxane as a useful strategy for cardio-protection in children undergoing anthracycline based treatment. However, large randomized trials are needed to confirm the cardio-protective role of Dexrazoxane in pediatric setting at long-term follow-up.
Jack C Yalowich - One of the best experts on this subject based on the ideXlab platform.
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the catalytic dna topoisomerase ii inhibitor Dexrazoxane icrf 187 induces differentiation and apoptosis in human leukemia k562 cells
Molecular Pharmacology, 2001Co-Authors: Brian B Hasinoff, Michael E Abram, Norman Barnabe, William P Allan, Tayeb Khelifa, Jack C YalowichAbstract:The bisdioxopiperazines ICRF-187 (Dexrazoxane), ICRF-193, and ICRF-154 are catalytic noncleavable complex-forming inhibitors of DNA topoisomerase II that do not produce protein-linked DNA strand breaks. In this study, we showed that bisdioxopiperazines induced erythroid differentiation, inhibited human leukemia K562 cell growth, and caused a slow induction of apoptosis. Dexrazoxane treatment caused DNA endoreduplication resulting in large highly polyploid cells. This result suggested the lack of a DNA topoisomerase II activity-based cell cycle checkpoint. The percentage of K562 cells that became apoptotic was much larger than the percentage of cells that stained for hemoglobin, suggesting that prior differentiation was not required for induction of apoptosis. Use of the Bcr-Abl tyrosine kinase inhibitor STI-571 resulted in a reduction in Bcl-xL levels and potentiation of Dexrazoxane-induced apoptosis related to an earlier onset and more extensive cleavage of caspase-3. These results indicated that Dexrazoxane-induced apoptosis is associated with a caspase-3 activation/cleavage pathway. In addition, these results were consistent with the antiapoptotic signaling function of Bcr-Abl to regulate expression of Bcl-xL. The ability of Dexrazoxane to induce differentiation and apoptosis suggests that bisdioxopiperazines may be useful in treating some types of leukemia.
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the catalytic dna topoisomerase ii inhibitor Dexrazoxane icrf 187 induces endopolyploidy in chinese hamster ovary cells
Journal of Pharmacology and Experimental Therapeutics, 2000Co-Authors: Brian B Hasinoff, Victor J Ferrans, Michael E Abram, Gaiklean Chee, Erwin Huebner, Edward H Byard, Norman Barnabe, Zuxi Yu, Jack C YalowichAbstract:The bisdioxopiperazines, including Dexrazoxane (ICRF-187), are catalytic or noncleavable complex-forming inhibitors of DNA topoisomerase II that do not produce DNA strand breaks. In this study we show that Dexrazoxane inhibits the division of Chinese hamster ovary (CHO) cells resulting in marked increases in cell size (up to 80 μm in diameter), volume (up to 150-fold greater), and ploidy (as high as 32N). This last result indicates that the Dexrazoxane-induced DNA reduplication was restricted to once per cell cycle. Kinetic analysis of the flow cytometry data indicated that the conversion between successively higher ploidy levels was progressively slowed at longer times of exposure to Dexrazoxane. Both the protein and DNA content of Dexrazoxane-treated CHO cells increased linearly over time in the same proportion. Light and electron microscopic studies of Dexrazoxane-treated cells showed ring-like multilobulated nuclei. Immunohistochemical staining of Dexrazoxane-treated cells showed that F-actin and acetylated α-tubulin were present in large, highly organized networks. Immunohistochemical staining of the Dexrazoxane-treated CHO cells also showed that the topoisomerase IIα colocalized with the DNA of the multilobulated nuclei. Staining of γ-tubulin revealed that the Dexrazoxane-treated cells contained multiple centrosomes, indicating that Dexrazoxane prevents cytokinesis but not centrosome reduplication. It is concluded that Dexrazoxane inhibits CHO cytokinesis in cells by virtue of its ability to inhibit topoisomerase II.
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mitindomide is a catalytic inhibitor of dna topoisomerase ii that acts at the bisdioxopiperazine binding site
Molecular Pharmacology, 1997Co-Authors: Brian B Hasinoff, Andrew M Creighton, Hanna Kozlowska, Padmakumari Thampatty, William P Allan, Jack C YalowichAbstract:The antitumor drug mitindomide (NSC 284356) was shown to inhibit the decatenation activity of human and Chinese hamster ovary (CHO) topoisomerase II [DNA topoisomerase (ATP-hydrolyzing), EC 5.99.1.1]. Mitindomide did not induce the formation of topoisomerase II-DNA covalent cleavable complexes in CHO cells. These results taken together indicate that mitindomide is a catalytic/noncleavable complex-forming-type inhibitor of topoisomerase II. The growth inhibitory effects of mitindomide and Dexrazoxane toward a sensitive parent CHO cell line and the Dexrazoxane-resistant DZR cell line, which is highly (500-fold) resistant to the bisdioxopiperazine Dexrazoxane, were measured. The DZR cell line was shown to be 30-fold cross-resistant to mitindomide. Mitindomide, like Dexrazoxane, was shown to inhibit cleavable complex formation by the topoisomerase II poison etoposide. The attenuated inhibition of etoposide-induced cleavable complexes in DZR compared with CHO cells was, likewise, very similar for Dexrazoxane and mitindomide. Together these results suggest that mitindomide acts at the same site on topoisomerase II as does Dexrazoxane and other bisdioxopiperazines. Various molecular parameters obtained by molecular modeling were compared for mitindomide and Dexrazoxane. Mitindomide, which is conformationally very rigid, has highly coplanar imide rings, as does Dexrazoxane in the solid state. Other molecular parameters, such as the imide nitrogen-to-imide nitrogen bond distances, and polar and nonpolar surface areas were also very similar. Thus, it is concluded that mitindomide exerts its antitumor effects through its inhibition of topoisomerase II by binding to the bisdioxopiperazine binding site.
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The effect of Dexrazoxane (ICRF-187) on doxorubicin- and daunorubicin-mediated growth inhibition of Chinese hamster ovary cells.
Anti-cancer drugs, 1996Co-Authors: Brian B Hasinoff, Jack C Yalowich, Yangzhi Ling, Joan L. BussAbstract:Dexrazoxane (ICRF-187) is clinically used to reduce doxorubicin-induced cardiotoxicity. Because Dexrazoxane, doxorubicin and daunorubicin all act on DNA topoisomerase II, a study was undertaken to see what effect Dexrazoxane had on the growth inhibitory effects of doxorubicin and daunorubicin towards Chinese hamster ovary cells. Dexrazoxane exhibited significant antagonism of doxorubicin- and daunorubicin-mediated growth inhibition when the cells were preincubated with Dexrazoxane before the anthracycline was added. Continuous exposure of cells to either anthracycline and low concentrations of Dexrazoxane resulted in additive growth inhibitory effects at low anthracycline concentrations, and no effect at higher anthracycline concentrations.