-
Clinical Cancer Research : An Official... Jul 2021Few prospective studies have assessed anthracycline-associated cardiotoxicity in patients with sarcoma. We evaluated cardiotoxicity in patients with soft-tissue sarcomas... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Few prospective studies have assessed anthracycline-associated cardiotoxicity in patients with sarcoma. We evaluated cardiotoxicity in patients with soft-tissue sarcomas administered doxorubicin in the phase III ANNOUNCE trial (NCT02451943).
PATIENTS AND METHODS
Patients were anthracycline-naïve adults with locally advanced or metastatic disease and left ventricular ejection fraction (LVEF) ≥50%. Patients could receive eight cycles of doxorubicin at 75 mg/m. The cardioprotectant, dexrazoxane, was allowed at investigator discretion. Symptomatic cardiac adverse events (AEs) were recorded using Medical Dictionary for Regulatory Activities and graded using Common Terminology Criteria for Adverse Events 4.0. LVEF deterioration was measured by echocardiogram or multigated acquisition scan, defined as a decrease to <50%, or decrease from baseline value >10%.
RESULTS
A total of 504 patients received ≥1 cycles of doxorubicin [median cumulative dose, 450.3 mg/m (range, 72.3-634.0)]. Median follow-up of cardiac AEs was 28 weeks. Dexrazoxane was coadministered more frequently to patients receiving higher cumulative doxorubicin doses (38.6% receiving <450 mg/m, 88.5% receiving 450-<600 mg/m, and 90% receiving ≥600 mg/m) and did not affect treatment efficacy. LVEF deterioration was seen in 62 of 153 (40.5%) patients who received a cumulative dose <450 mg/m, 82 of 159 patients (51.6%) who received 450-<600 mg/m, and 50 of 89 patients (56.2%) who received ≥600 mg/m. Grade ≥3 cardiac dysfunction occurred in 2% of patients at <450 mg/m, 3% at 450-<600 mg/m, and 1.1% at ≥600 mg/m. Incidence of treatment-related cardiac AEs was low across all dose ranges.
CONCLUSIONS
Although follow-up was short, these results suggest doxorubicin can be administered at high cumulative doses (>450 mg/m), with a low rate of cardiotoxicities, in the context of dexrazoxane coadministration..
Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Cardiotoxicity; Double-Blind Method; Doxorubicin; Female; Humans; Male; Middle Aged; Neoplasm Staging; Prospective Studies; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms; Ventricular Function, Left
PubMed: 33632930
DOI: 10.1158/1078-0432.CCR-20-4592 -
Scientific Reports Feb 2021The bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 has been previously identified as a more potent analog of dexrazoxane (ICRF-187), a drug used in clinical...
Development of water-soluble prodrugs of the bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 as potential cardioprotective agents against anthracycline cardiotoxicity.
The bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 has been previously identified as a more potent analog of dexrazoxane (ICRF-187), a drug used in clinical practice against anthracycline cardiotoxicity. However, the poor aqueous solubility of ICRF-193 has precluded its further in vivo development as a cardioprotective agent. To overcome this issue, water-soluble prodrugs of ICRF-193 were prepared, their abilities to release ICRF-193 were investigated using a novel UHPLC-MS/MS assay, and their cytoprotective effects against anthracycline cardiotoxicity were tested in vitro in neonatal ventricular cardiomyocytes (NVCMs). Based on the obtained results, the bis(2-aminoacetoxymethyl)-type prodrug GK-667 was selected for advanced investigations due to its straightforward synthesis, sufficient solubility, low cytotoxicity and favorable ICRF-193 release. Upon administration of GK-667 to NVCMs, the released ICRF-193 penetrated well into the cells, reached sufficient intracellular concentrations and provided effective cytoprotection against anthracycline toxicity. The pharmacokinetics of the prodrug, ICRF-193 and its rings-opened metabolite was estimated in vivo after administration of GK-667 to rabbits. The plasma concentrations of ICRF-193 reached were found to be adequate to achieve cardioprotective effects in vivo. Hence, GK-667 was demonstrated to be a pharmaceutically acceptable prodrug of ICRF-193 and a promising drug candidate for further evaluation as a potential cardioprotectant against chronic anthracycline toxicity.
Topics: Animals; Anthracyclines; Cardiotonic Agents; Cardiotoxicity; DNA Topoisomerases, Type II; Dexrazoxane; Diketopiperazines; Male; Myocytes, Cardiac; Piperazine; Prodrugs; Rabbits; Razoxane; Topoisomerase II Inhibitors; Water
PubMed: 33627707
DOI: 10.1038/s41598-021-83688-x -
Current Treatment Options in Oncology Feb 2021Heart failure (HF) is increasingly recognized as the major complication of chemotherapy regimens. Despite the development of modern targeted therapies such as monoclonal... (Review)
Review
Heart failure (HF) is increasingly recognized as the major complication of chemotherapy regimens. Despite the development of modern targeted therapies such as monoclonal antibodies, doxorubicin (DOXO), one of the most cardiotoxic anticancer agents, still remains the treatment of choice for several solid and hematological tumors. The insurgence of cardiotoxicity represents the major limitation to the clinical use of this potent anticancer drug. At the molecular level, cardiac side effects of DOXO have been associated to mitochondrial dysfunction, DNA damage, impairment of iron metabolism, apoptosis, and autophagy dysregulation. On these bases, the antioxidant and iron chelator molecule, dexrazoxane, currently represents the unique FDA-approved cardioprotectant for patients treated with anthracyclines.A less explored area of research concerns the impact of DOXO on cardiac metabolism. Recent metabolomic studies highlight the possibility that cardiac metabolic alterations may critically contribute to the development of DOXO cardiotoxicity. Among these, the impairment of oxidative phosphorylation and the persistent activation of glycolysis, which are commonly observed in response to DOXO treatment, may undermine the ability of cardiomyocytes to meet the energy demand, eventually leading to energetic failure. Moreover, increasing evidence links DOXO cardiotoxicity to imbalanced insulin signaling and to cardiac insulin resistance. Although anti-diabetic drugs, such as empagliflozin and metformin, have shown interesting cardioprotective effects in vitro and in vivo in different models of heart failure, their mechanism of action is unclear, and their use for the treatment of DOXO cardiotoxicity is still unexplored.This review article aims at summarizing current evidence of the metabolic derangements induced by DOXO and at providing speculations on how key players of cardiac metabolism could be pharmacologically targeted to prevent or cure DOXO cardiomyopathy.
Topics: Anthracyclines; Antineoplastic Agents; Autophagy; Biomarkers; Cardiotoxicity; Cell Survival; Disease Susceptibility; Fatty Acids; Glycolysis; Humans; Insulin Resistance; Iron; Myocardium; Myocytes, Cardiac; Neoplasms; Oxidation-Reduction
PubMed: 33547494
DOI: 10.1007/s11864-020-00812-1 -
Cellular and Molecular Life Sciences :... Apr 2021Doxorubicin (DOX) is an anthracycline chemotherapy drug used in the treatment of various types of cancer. However, short-term and long-term cardiotoxicity limits the... (Review)
Review
Doxorubicin (DOX) is an anthracycline chemotherapy drug used in the treatment of various types of cancer. However, short-term and long-term cardiotoxicity limits the clinical application of DOX. Currently, dexrazoxane is the only approved treatment by the United States Food and Drug Administration to prevent DOX-induced cardiotoxicity. However, a recent study found that pre-treatment with dexrazoxane could not fully improve myocardial toxicity of DOX. Therefore, further targeted cardioprotective prophylaxis and treatment strategies are an urgent requirement for cancer patients receiving DOX treatment to reduce the occurrence of cardiotoxicity. Accumulating evidence manifested that Sirtuin 1 (SIRT1) could play a crucially protective role in heart diseases. Recently, numerous studies have concentrated on the role of SIRT1 in DOX-induced cardiotoxicity, which might be related to the activity and deacetylation of SIRT1 downstream targets. Therefore, the aim of this review was to summarize the recent advances related to the protective effects, mechanisms, and deficiencies in clinical application of SIRT1 in DOX-induced cardiotoxicity. Also, the pharmaceutical preparations that activate SIRT1 and affect DOX-induced cardiotoxicity have been listed in this review.
Topics: Animals; Antibiotics, Antineoplastic; Cardiotoxicity; Doxorubicin; Humans; Signal Transduction; Sirtuin 1
PubMed: 33438055
DOI: 10.1007/s00018-020-03729-y -
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 -
BMC Cancer Nov 2020The recommended cumulative doxorubicin dose in soft tissue sarcoma (STS) treatment was based on cardiotoxicity data from retrospective studies of breast cancer patients....
BACKGROUND
The recommended cumulative doxorubicin dose in soft tissue sarcoma (STS) treatment was based on cardiotoxicity data from retrospective studies of breast cancer patients. However, the treatment and prognosis of STS and breast cancer are quite different, and reference to breast cancer data alone may not reflect the efficacy of doxorubicin treatment in STS. This study, thus, aimed to review and analyze clinical data of STS patients treated with a high cumulative doxorubicin dose, to provide a reference for treatment selection and clinical trial design.
METHODS
We retrospectively collected and analyzed clinical data of patients with advanced STS who received doxorubicin-based chemotherapy from January 2016 to January 2020. The patients were divided into a standard-dose group (who received ≤6 cycles of doxorubicin after the initial diagnosis) and an over-dose group (who were re-administered doxorubicin [doxorubicin-rechallenge] after receiving 6 cycles of doxorubicin therapy discontinuously). Patient characteristics, cumulative doxorubicin dose, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), cardiotoxicity incidence, and treatment effectiveness were evaluated in both groups.
RESULTS
A total of 170 patients with advanced STS were recruited (146 in the standard-dose group and 24 in the over-dose group). The average cumulative doxorubicin dose was 364.04 ± 63.81 mg/m2 in the standard-dose group and 714.38 ± 210.09 mg/m2 in the over-dose group. The ORR, DCR, and median PFS were 15.07, 58.9%, and 6 (95% confidence interval [CI]: 5.8-6.5) months in the standard-dose group and 16.67, 66.67%, and 4 (95%CI: 2.0-5.8) months in the over-dose group, respectively. Symptomatic heart failure occurred in five patients (3.42%) of the standard-dose group and in one patient (4.17%) of the over-dose group. In these patients with cardiotoxicity, doxorubicin was discontinued, and all of them died of uncontrolled tumor growth. No drug-related deaths occurred.
CONCLUSIONS
The continuation of or rechallenge with doxorubicin beyond the recommended cumulative dose could be a promising therapeutic option in the treatment of chemotherapy-sensitive advanced sarcomas. Further evaluation is necessary in prospective trials.
Topics: Antibiotics, Antineoplastic; Doxorubicin; Female; Humans; Male; Sarcoma
PubMed: 33228579
DOI: 10.1186/s12885-020-07663-x -
Redox Biology Oct 2020Overproduction of reactive oxygen species (ROS) is a well-established indicator of ongoing tissue inflammation. However, there is a scarcity of molecular imaging probes...
Overproduction of reactive oxygen species (ROS) is a well-established indicator of ongoing tissue inflammation. However, there is a scarcity of molecular imaging probes capable of providing noninvasive sensitive detection of ROS for allowing longitudinal studies of disease pathology and/or monitoring therapeutic efficacy of ROS scavengers. Herein, we report synthesis and chemical characterization of a novel metalloprobe, Galuminox, a moderately fluorescent agent that detects superoxide and hydrogen peroxide generation. Using live-cell fluorescence imaging analysis, Galuminox demonstrates ability to detect superoxide and monitor effects of ROS-attenuating agents, such as Carvedilol, Dexrazoxane, and mitoTempo in lung epithelial A549 cells. Furthermore, LPS stimulation of A549 cells that either express the mitochondria targeted fluorescent protein Keima or are stained with MitoSOX, a mitochondria-specific superoxide probe, indicates preferential co-localization of Galuminox with mitochondria producing elevated amounts of superoxide. Dynamic PET/CT scans 45 min post tail-vein administration of Ga-Galuminox show 4-fold higher uptake and stable retention in lungs of LPS treated mice compared to their saline-only treated counterparts. Post preclinical PET imaging, quantitative biodistribution studies also correlate with 4-fold higher retention of the radiotracer in lungs of LPS treated mice compared with their saline-only treated control counterparts. Consistent with these observations, lung cells isolated from LPS-treated mice demonstrated elevated ROS production deploying CellROX, the ROS probe. Finally, Galuminox uptake correlates with histological and physiological evidence of acute lung injury as evident by polynuclear infiltration, thickening of the alveolar epithelial membranes and increased bronchioalveolar lavage protein content. Taken collectively, these data indicate that Ga-Galuminox tracer uptake is a measure of ROS activity in acutely injured lungs and suggests its potential utility in monitoring oxidative stress in other diseases.
Topics: Animals; Mice; Oxidative Stress; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Reactive Oxygen Species; Tissue Distribution
PubMed: 33039825
DOI: 10.1016/j.redox.2020.101690 -
Cells Sep 2020Doxorubicin (DOX) is an anticancer drug widely used in oncology, especially for breast cancer. The main limitation of DOX treatment is its cardiotoxicity due to the...
GPR91 Receptor Mediates Protection against Doxorubicin-Induced Cardiotoxicity without Altering Its Anticancer Efficacy. An In Vitro Study on H9C2 Cardiomyoblasts and Breast Cancer-Derived MCF-7 Cells.
Doxorubicin (DOX) is an anticancer drug widely used in oncology, especially for breast cancer. The main limitation of DOX treatment is its cardiotoxicity due to the cumulative dose. Clinically, DOX-induced cardiomyopathy develops as a progressive heart failure caused by a progressive cardiomyocyte's death. For long, the oxidative stress induced by DOX was considered as the main toxic mechanism responsible for heart damage, but it is now controverted, and other processes are investigated to develop cardioprotective strategies. Previously, we studied DOX-induced cardiotoxicity and dexrazoxane (DEX), the only cardioprotective compound authorized by the FDA, by H-NMR metabonomics in H9C2 cells. We observed an increased succinate secretion in the extracellular fluid of DEX-exposed cardiomyocytes, a finding that led us to the hypothesis of a possible protective role of this agonist of the GPR91 receptor. The objective of the present work was to study the effect of succinate (SUC) and epoxysuccinate (-ES), two agonists of the GPR91 receptor, on DOX-induced cardiotoxicity to H9C2 cells. To this purpose, several toxicity parameters, including cell viability, oxidative stress and apoptosis, as well as the GPR91 expression, were measured to assess the effects of DEX, SUC and -ES either alone or in combination with DOX in H9C2 cells. A H-NMR-based metabonomic study was carried out on cellular fluids collected after 24 h to highlight the metabolic changes induced by those protective compounds. Moreover, the effects of each agonist given either alone or in combination with DOX were evaluated on MCF-7 breast cancer cells. GPR91 expression was confirmed in H9C2 cells, while no expression was found in MCF-7 cells. Under such experimental conditions, both SUC and -ES decreased partially the cellular mortality, the oxidative stress and the apoptosis induced by DOX. The SUC protective effect was similar to the DEX effect, but the protective effect of -ES was higher on oxidative stress and apoptosis. In addition, the metabonomics findings pointed out several metabolic pathways involved in the cardioprotective effects of both GPR91 agonists: the stimulation of aerobic metabolism with glucose as the main fuel, redox balance and phospholipids synthesis. Finally, none of the GPR91 agonists jeopardized the pharmacological effects of DOX on MCF-7 breast cancer cells.
Topics: Animals; Apoptosis; Breast Neoplasms; Cardiotoxicity; Cell Respiration; Cell Survival; Doxorubicin; Female; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Myoblasts, Cardiac; Oxidative Stress; Rats; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 32992522
DOI: 10.3390/cells9102177 -
Journal of Enzyme Inhibition and... Dec 2020The significant role of topoisomerases in the control of DNA chain topology has been confirmed in numerous research conducted worldwide. The prevalence of these enzymes,... (Review)
Review
The significant role of topoisomerases in the control of DNA chain topology has been confirmed in numerous research conducted worldwide. The prevalence of these enzymes, as well as the key importance of topoisomerase in the proper functioning of cells, have made them the target of many scientific studies conducted all over the world. This article is a comprehensive review of knowledge about topoisomerases and their inhibitors collected over the years. Studies on the structure-activity relationship and molecular docking are one of the key elements driving drug development. In addition to information on molecular targets, this article contains details on the structure-activity relationship of described classes of compounds. Moreover, the work also includes details about the structure of the compounds that drive the mode of action of topoisomerase inhibitors. Finally, selected topoisomerases inhibitors at the stage of clinical trials and their potential application in the chemotherapy of various cancers are described.
Topics: Acridines; Animals; Antineoplastic Agents; DNA Topoisomerases; Dexrazoxane; Drug Screening Assays, Antitumor; Humans; Molecular Docking Simulation; Quinolones; Structure-Activity Relationship; Thiobarbiturates; Topoisomerase Inhibitors
PubMed: 32975138
DOI: 10.1080/14756366.2020.1821676