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Pharmacology 2022Doxorubicin (DOX), an anthracycline antitumor agent, has been widely used against various solid tumors and hematological malignancies. However, the clinical application...
INTRODUCTION
Doxorubicin (DOX), an anthracycline antitumor agent, has been widely used against various solid tumors and hematological malignancies. However, the clinical application of DOX is restricted by its multiple organ toxicity including nephrotoxicity. This study investigated the protective effects and mechanisms of dexrazoxane (DZR) against DOX-induced nephropathy in rats.
METHODS
Male Sprague Dawley rats received 2.5 mg/kg DOX once a week for 5 consecutive weeks. 24-h urinary protein and renal function injury biomarkers were determined to evaluate the renal function. Histopathological changes and glomerulosclerosis were examined by hematoxylin and eosin and periodic acid-Schiff staining. The change of renal ultrastructure in the DOX-induced rats was observed by the electron microscopy. The renal apoptosis was detected by TUNEL staining and measured the protein expression of Caspase-3, Bcl-2, and Bax. Renal interstitial fibrosis was determined by Masson staining and immunohistochemistry examination. The levels of vimentin, alpha-smooth muscle actin (α-SMA), and transforming growth factor β (TGF-β) in kidney tissue were detected by Western blot.
RESULTS
DZR pretreatment markedly raised the survival rate and improved the renal dysfunction in DOX-treated rats. DZR ameliorated DOX-induced histopathological lesion of glomerular and tubular and apoptosis. DZR restored the oxidant/antioxidant balance via regulating the levels of MDA, SOD, and TAC. DZR reduced DOX-induced collagen IV deposition and renal interstitial fibrosis and downregulated the fibrosis-related protein expressions of vimentin, α-SMA, and TGF-β1.
CONCLUSION
Our results suggest DZR exerted its protective effects against DOX-induced nephropathy through inhibition of lipid peroxidation, apoptosis, and fibrosis.
Topics: Animals; Antibiotics, Antineoplastic; Dexrazoxane; Doxorubicin; Fibrosis; Kidney; Kidney Diseases; Male; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta1
PubMed: 35021174
DOI: 10.1159/000521220 -
Clinical & Translational Oncology :... Jan 2014Extravasation of cytotoxic agents is a true medical emergency. Dexrazoxane is the only licensed drug for the treatment of anthracycline extravasations. Dexrazoxane... (Review)
Review
Extravasation of cytotoxic agents is a true medical emergency. Dexrazoxane is the only licensed drug for the treatment of anthracycline extravasations. Dexrazoxane proved to be effective and moderately well tolerated. However, alternative approaches for the management of anthracycline extravasations are available such as topical DMSO and cooling. There appears to be general agreement about dexrazoxane usefulness when extravasations involve large volumes of anthracycline and/or central venous access device. Nevertheless, the non-invasive combination of DMSO and cooling is the most commonly described therapy, particularly in small anthracycline extravasations. Further research is still needed to establish unequivocal situations where dexrazoxane must be initiated.
Topics: Animals; Anthracyclines; Antineoplastic Agents; Dexrazoxane; Extravasation of Diagnostic and Therapeutic Materials; Humans; Infusions, Intravenous
PubMed: 23949792
DOI: 10.1007/s12094-013-1100-7 -
Cureus Apr 2023Cancer is one of the leading causes of morbidity and mortality in the pediatric population with the most common cancer being acute lymphoblastic leukemia. One of the... (Review)
Review
Cancer is one of the leading causes of morbidity and mortality in the pediatric population with the most common cancer being acute lymphoblastic leukemia. One of the most common drugs used in the treatment is the anthracycline group of chemotherapeutic agents, and a major side effect is cardiotoxicity. Dexrazoxane, a member of the cardioprotective agents' group of medications, is the only current FDA-approved medication to tackle cardiotoxicity. The mechanism of action in which dexrazoxane is cardioprotective is by halting necroptosis in cardiomyocytes after anthracycline therapy and concurrently binds with iron and reduces the formation of anthracycline-iron complexes and reactive oxygen species. The efficacy of dexrazoxane has been demonstrated in clinical trials within the pediatric population with roughly 60%-80% reduction in risk of developing cardiotoxicity with a very tolerable and limited side effect profile. Further research is required to not only establish the efficacy of dexrazoxane within the pediatric population but also to explore other medications that may serve alongside the function of dexrazoxane.
PubMed: 37182052
DOI: 10.7759/cureus.37308 -
Journal of Pediatric Oncology Nursing :... 2015Anthracyclines are a fundamental part of many childhood cancer therapy regimens; however, the discovery of anthracycline-induced cardiotoxicity has raised concern and... (Review)
Review
Anthracyclines are a fundamental part of many childhood cancer therapy regimens; however, the discovery of anthracycline-induced cardiotoxicity has raised concern and led to dose limitation. The cardiotoxicity of anthracyclines has resulted in an increased demand for cardioprotectants. Dexrazoxane is the only cardioprotectant that has proven efficacy in reducing cardiotoxic effects when given prior to the administration of anthracyclines. Currently, it is still considered an "off-label" use due to a paucity of data in the literature on dexrazoxane administration in children. Nevertheless, through evaluation of the available data, dexrazoxane is observed to be safe, tolerable, and efficacious in mitigating the cardiotoxic effects of anthracycline in children, without jeopardizing its antineoplastic activity or increasing the risk of developing secondary malignant neoplasms.
Topics: Adolescent; Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Agents; Cardiotoxicity; Child; Child, Preschool; Dexrazoxane; Female; Humans; Infant; Male; Neoplasms; Protective Agents
PubMed: 25366577
DOI: 10.1177/1043454214554008 -
Cancer Management and Research 2014For more than half a century, the different properties of dexrazoxane have captured the attention of scientists and clinicians. Presently, dexrazoxane is licensed in... (Review)
Review
For more than half a century, the different properties of dexrazoxane have captured the attention of scientists and clinicians. Presently, dexrazoxane is licensed in many parts of the world for two different indications: prevention of cardiotoxicity from anthracycline-based chemotherapy, and prevention of tissue injuries after extravasation of anthracyclines. This article reviews the historical, preclinical, and clinical background for the use of dexrazoxane for these indications.
PubMed: 25246808
DOI: 10.2147/CMAR.S47238 -
Biomedicine & Pharmacotherapy =... Sep 2023Doxorubicin, a member of the anthracycline family, is a widely prescribed anticancer chemotherapy drug. Unfortunately, cumulative doses of doxorubicin can cause...
Doxorubicin, a member of the anthracycline family, is a widely prescribed anticancer chemotherapy drug. Unfortunately, cumulative doses of doxorubicin can cause mitochondrial dysfunction, leading to acute or chronic cardiotoxicity. This study demonstrated that Neopetroside-B (NPS-B) protects cardiomyocytes in the presence of doxorubicin. NPS-B improved mitochondrial function in cardiomyocytes by increasing ATP production and oxygen consumption rates. On the other hand, NPS-B negatively influenced cancer cell lines by increasing reactive oxygen species. We analyzed NPS-B-influenced metabolites (VIP > 1.0; AUC>0.7; p < 0.05) and proteins (FC > 2.0) and constructed metabolite-protein enrichment, which showed that NPS-B affected uracil metabolism and NAD-binding proteins (e.g., aldehyde dehydrogenase and glutathione reductase) in cardiomyocytes. However, for the cancer cells, NPS-B decreased the NAD/NADH balance, impairing cell viability. In a xenograft mouse model treated with doxorubicin, NPS-B reduced cardiac fibrosis and improved cardiac function. NPS-B may be a beneficial intervention to reducing doxorubicin-induced cardiotoxicity with anticancer effects.
Topics: Humans; Mice; Animals; Cardiotoxicity; NAD; Doxorubicin; Antibiotics, Antineoplastic; Antineoplastic Agents; Myocytes, Cardiac; Mitochondria
PubMed: 37523986
DOI: 10.1016/j.biopha.2023.115232 -
JACC. CardioOncology Apr 2024
PubMed: 38773999
DOI: 10.1016/j.jaccao.2024.02.004 -
Journal of Clinical Oncology : Official... Aug 2015
Topics: Dexrazoxane; Female; Hodgkin Disease; Humans; Male; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 26195707
DOI: 10.1200/JCO.2015.61.7928 -
Future Oncology (London, England) Oct 2018Dexrazoxane can prevent anthracycline-associated cardiotoxicity. However, in 2011, its use in children was contraindicated by the EMA over concerns of increased risk of... (Review)
Review
Dexrazoxane can prevent anthracycline-associated cardiotoxicity. However, in 2011, its use in children was contraindicated by the EMA over concerns of increased risk of infection, myelosuppression and second primary malignancies, and because its efficacy in children had not then been established. We review here the evidence published since 2011, which confirms that dexrazoxane is an effective cardioprotectant in children and adolescents, is not associated with an increased risk of second primary malignancies or excess early or late mortality and does not impair chemotherapy efficacy. Based on this evidence, the contraindication for children and adolescents requiring high doses of anthracyclines and at risk for cardiotoxicity was removed from the European labeling for dexrazoxane.
Topics: Adolescent; Anthracyclines; Antibiotics, Antineoplastic; Cardiotoxicity; Child; Dexrazoxane; Humans; Neoplasms, Second Primary
PubMed: 29747541
DOI: 10.2217/fon-2018-0210 -
Aging Jan 2021Treatment of thoracic tumors with radiotherapy can lead to severe cardiac injury. We investigated the effects of dexrazoxane, a USFDA-approved cardioprotective drug...
Treatment of thoracic tumors with radiotherapy can lead to severe cardiac injury. We investigated the effects of dexrazoxane, a USFDA-approved cardioprotective drug administered with chemotherapy, on radiation-induced heart disease (RIHD) in a rat model. Male Sprague-Dawley rats were irradiated with a single dose of 20 Gy to the heart and treated with dexrazoxane at the time of irradiation and for 12 subsequent weeks. Dexrazoxane suppressed radiation-induced myocardial apoptosis and significantly reversed changes in serum cardiac troponin I levels and histopathological characteristics six months post-radiation. Treatment with dexrazoxane did not alter the radiosensitivity of thoracic tumors in a tumor formation experiment using male nude Balb/C mice with tumors generated by H292 cells. Dexrazoxane reduced the accumulation of reactive oxygen species in rat cardiac tissues, but not in tumors in nude mice. Transcriptome sequencing showed that and , which are involved in Toll-like receptor signaling, may be associated with the anti-RIHD effects of dexrazoxane. Immunohistochemistry revealed that dexrazoxane significantly decreased NF-κB p65 expression in cardiomyocytes. These findings suggest dexrazoxane may protect against RIHD by suppressing apoptosis and oxidative stress in cardiomyocytes.
Topics: Animals; Apoptosis; Dexrazoxane; Heart; Heart Diseases; Male; Mice; Mice, Nude; Protective Agents; Radiation Injuries, Experimental; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species
PubMed: 33406500
DOI: 10.18632/aging.202332