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Oxidative Medicine and Cellular... 2022
Topics: Anthracyclines; Antibiotics, Antineoplastic; Autophagy; Cardiotoxicity; Humans; Inflammation; Neoplasms; Oxidative Stress
PubMed: 35464757
DOI: 10.1155/2022/9862524 -
Redox Biology Jan 2020Doxorubicin (DOX), or Adriamycin, an anthracycline antibiotic discovered serendipitously as a chemotherapeutic drug several decades ago, is still one of the most... (Review)
Review
Doxorubicin (DOX), or Adriamycin, an anthracycline antibiotic discovered serendipitously as a chemotherapeutic drug several decades ago, is still one of the most effective drugs for treating various adult and pediatric cancers (breast cancer, Hodgkin's disease, lymphoblastic leukemia). However, one of the major side effects of the continuous use of DOX is dose-dependent, long-term, and potentially lethal cardiovascular toxicity (congestive heart failure and cardiomyopathy) in cancer survivors many years after cessation of chemotherapy. In addition, predisposition to cardiotoxicity varied considerably among individuals. The long-held notion that DOX cardiotoxicity is caused by reactive oxygen species formed from the redox-cycling of DOX semiquinone lacks rigorous proof in a chronic animal model, and administration of reactive oxygen species detoxifying agents failed to reverse DOX-induced cardiac problems. In this review, I discuss the pros and cons of the reactive oxygen species pathway as a primary or secondary mechanism of DOX cardiotoxicity, the role of topoisomerases, and the potential use of mitochondrial-biogenesis-enhancing compounds in reversing DOX-induced cardiomyopathy. New approaches for well-designed clinical trials that repurpose FDA-approved drugs and naturally occurring polyphenolic compounds prophylactically to prevent or mitigate cardiovascular complications in both pediatric and adult cancer survivors are needed. Essentially, the focus should be on enhancing mitochondrial biogenesis to prevent or mitigate DOX-induced cardiotoxicity.
Topics: Animals; Antibiotics, Antineoplastic; Cardiotoxicity; Child; Doxorubicin; Humans; Reactive Oxygen Species; Topoisomerase II Inhibitors
PubMed: 31790851
DOI: 10.1016/j.redox.2019.101394 -
Kardiologia Polska 2023
Topics: Humans; Pilot Projects; Anthracyclines; Microcirculation; Antibiotics, Antineoplastic
PubMed: 37190918
DOI: 10.33963/KP.a2023.0108 -
Acta Pharmaceutica (Zagreb, Croatia) Mar 2021Substances available in nature with potential therapeutic effects are the subject of research that raises tremendous hopes for new challenges in medicine. Fungi are the... (Review)
Review
Substances available in nature with potential therapeutic effects are the subject of research that raises tremendous hopes for new challenges in medicine. Fungi are the most common organisms in the ecosystem and the most interesting in this respect. This review discusses two species of edible fungi, used for centuries in Eastern natural medicine, with the best-documented effect - Hericium erinaceus (He) and Trametes versicolor (Tv). The results of in vivo and in vitro studies conducted on mice and human cell lines demonstrate immunomodulatory, potentially, anticancer, anti-inflammatory and neuroregenerative effects of substances isolated from these fungi. The substances contained in the extracts of He and Tv seem to have immunomodulatory effects that may support chemotherapy. The use of these extracts is justified stronger than the other supportive treat ments based on supplements.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antibiotics, Antineoplastic; Cell Line, Tumor; Hericium; Humans; Immunologic Factors; Mice; Neurodegenerative Diseases; Polyporaceae
PubMed: 32697746
DOI: 10.2478/acph-2021-0007 -
Medicine Nov 2023There have been controversial findings from recent studies regarding anthracyclines use and the subsequent risk of arrhythmias. This study aimed to evaluate the existing... (Meta-Analysis)
Meta-Analysis
BACKGROUND
There have been controversial findings from recent studies regarding anthracyclines use and the subsequent risk of arrhythmias. This study aimed to evaluate the existing evidence of the risk of arrhythmias in patients treated with anthracyclines.
METHODS
PubMed, Scopus, and Web of Science databases were searched up to April 2022 using keywords such as "anthracycline" and "arrhythmia." Dichotomous data were presented as relative risk (RR) and confidence interval (CI), while continuous data were presented as mean difference (MD) and CI. Revman software version 5.4 was used for the analysis.
RESULTS
Thirteen studies were included with a total of 26891 subjects. Pooled analysis showed that anthracyclines therapy was significantly associated with a higher risk of arrhythmia (RR: 1.58; 95% CI: 1.41-1.76; P < .00001), ST segment and T wave abnormalities (RR: 1.73, 95% CI: 1.18-2.55, P = .005), conduction abnormalities and AV block (RR = 1.86, 95% CI = 1.06-3.25, P = .03), and tachycardia (RR: 1.736, 95% CI: 1.11-2.69, P = .02). Further analyses of the associations between anthracyclines and atrial flutter (RR = 1.30, 95% CI = 0.29-5.89, P = .74), atrial ectopic beats (RR: 1.27, 95% CI: 0.78-2.05, P = .34), and ventricular ectopic beats (RR: 0.93, 95% CI: 0.53-1.65, P = .81) showed no statistically significant results. Higher doses of anthracycline were associated with a higher risk of arrhythmias (RR: 1.49; 95% CI: 1.08-2.05; P = .02) compared to the lower doses (RR: 1.36; 95% CI: 1.00-1.85; P = .05). Newer generations of Anthracycline maintained the arrhythmogenic properties of previous generations, such as Doxorubicin.
CONCLUSION
Anthracyclines therapy was significantly associated with an increased risk of arrhythmias. Accordingly, Patients treated with anthracyclines should be screened for ECG abnormalities and these drugs should be avoided in patients susceptible to arrhythmia. The potential benefit of the administration of prophylactic anti-fibrotic and anti-arrhythmic drugs should also be explored.
Topics: Humans; Anthracyclines; Arrhythmias, Cardiac; Antibiotics, Antineoplastic; Doxorubicin; Tachycardia; Leukemia, Myeloid, Acute
PubMed: 37986405
DOI: 10.1097/MD.0000000000035770 -
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 -
European Review For Medical and... May 2023Doxorubicin (DOX) is a widely used cytotoxic anthracycline antibiotic characterized by increased adverse effects that limit its clinical usefulness. Pregnenolone is a...
Pregnenolone protects the liver against doxorubicin-induced cellular injury by anti-inflammatory, antioxidant, and antiapoptotic mechanisms: role of Keap1/Nrf2/HO-1 and P-glycoprotein.
OBJECTIVE
Doxorubicin (DOX) is a widely used cytotoxic anthracycline antibiotic characterized by increased adverse effects that limit its clinical usefulness. Pregnenolone is a pregnane X receptor (PXR) agonist that increases the expression of xenobiotic transporters with anti-inflammatory and antioxidant potential. Thus, we hypothesized that pregnenolone would protect against DOX-induced hepatotoxicity.
MATERIALS AND METHODS
Male Wistar rats (180-200 g) were randomized into four groups (n = 7): Control, Control + Pregnenolone (35 mg/kg/day, orally), DOX (15 mg/kg, i.p.) single dose on day five, and Pregnenolone + DOX. All treatments continued for seven consecutive days. Twenty-four hours after the last treatment, serum and liver tissues were collected for biochemical and histopathological assessment. The possible interaction between pregnenolone and DOX on cell viability was tested in HepG2 cells in vitro by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.
RESULTS
DOX treatment resulted in hepatic damage and fibrosis with increased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Liver samples of the DOX-treated group showed increased oxidative stress [malondialdehyde (MDA) and total nitrite/nitrate and decreased reduced glutathione (GSH) and superoxide dismutase (SOD)], increased hepatic tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), transforming growth factor-beta1 (TGF-β1), and mRNA of interleukin-1beta (IL-1β) and interleukin-6 (IL-6). Pretreating the rats with pregnenolone antagonized these DOX-induced effects. Moreover, pregnenolone upregulated the hepatic expression of Nrf2, heme oxygenase-1 (HO-1), and P-glycoprotein and decreased Keap1, opposing the effects of DOX. Moreover, pregnenolone prevented the DOX-induced activation and nuclear translocation of NFκB and increased cleaved caspase-3. Pregnenolone potentiated DOX-mediated cytotoxicity in HepG2 cells.
CONCLUSIONS
These results illustrate the protective effects of pregnenolone against DOX-induced hepatotoxicity without limiting its anticancer activity.
Topics: Animals; Male; Rats; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antioxidants; ATP Binding Cassette Transporter, Subfamily B, Member 1; Chemical and Drug Induced Liver Injury; Doxorubicin; Heme Oxygenase-1; Interleukin-6; Kelch-Like ECH-Associated Protein 1; Liver; NF-E2-Related Factor 2; Oxidative Stress; Rats, Wistar
PubMed: 37259756
DOI: 10.26355/eurrev_202305_32484 -
Drug Delivery Dec 2022Retinoblastoma (RB) is a malignant intraocular neoplasm that occurs in children. Diagnosis and therapy are frequently delayed, often leading to metastasis, which...
Retinoblastoma (RB) is a malignant intraocular neoplasm that occurs in children. Diagnosis and therapy are frequently delayed, often leading to metastasis, which necessitates effective imaging and treatment. In recent years, the use of nanoplatforms allowing both imaging and targeted treatment has attracted much attention. Herein, we report a novel nanoplatform folate-receptor (FR) targeted laser-activatable liposome termed FA-DOX-ICG-PFP@Lip, which is loaded with doxorubicin (DOX)/indocyanine green (ICG) and liquid perfluoropentane (PFP) for photoacoustic/ultrasound (PA/US) dual-modal imaging-guided chemo/photothermal RB therapy. The dual-modal imaging capability, photothermal conversion under laser irradiation, biocompatibility, and antitumor ability of these liposomes were appraised. The multifunctional liposome showed a good tumor targeting ability and was efficacious as a dual-modality contrast agent both and . When laser-irradiated, the liposome converted light energy to heat. This action caused immediate destruction of tumor cells, while simultaneously initiating PFP phase transformation to release DOX, resulting in both photothermal and chemotherapeutic antitumor effects. Notably, the FA-DOX-ICG-PFP@Lip showed good biocompatibility and no systemic toxicity was observed after laser irradiation in RB tumor-bearing mice. Hence, the FA-DOX-ICG-PFP@Lip shows great promise for dual-modal imaging-guided chemo/photothermal therapy, and may have significant value for diagnosing and treating RB.
Topics: Animals; Antibiotics, Antineoplastic; Cell Line, Tumor; Cell Survival; Chemistry, Pharmaceutical; Coloring Agents; Doxorubicin; Drug Carriers; Drug Liberation; Folic Acid Transporters; Humans; Indocyanine Green; Liposomes; Mice; Nanoparticles; Particle Size; Photoacoustic Techniques; Photothermal Therapy; Random Allocation; Retinal Neoplasms; Retinoblastoma; Surface Properties; Ultrasonography, Interventional; Xenograft Model Antitumor Assays
PubMed: 35156504
DOI: 10.1080/10717544.2022.2032876 -
JAMA Apr 2020Patients with advanced soft tissue sarcoma (STS) have a median overall survival of less than 2 years. In a phase 2 study, an overall survival benefit in this population... (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
Patients with advanced soft tissue sarcoma (STS) have a median overall survival of less than 2 years. In a phase 2 study, an overall survival benefit in this population was observed with the addition of olaratumab to doxorubicin over doxorubicin alone.
OBJECTIVE
To determine the efficacy of doxorubicin plus olaratumab in patients with advanced/metastatic STS.
DESIGN, SETTING, AND PARTICIPANTS
ANNOUNCE was a confirmatory, phase 3, double-blind, randomized trial conducted at 110 sites in 25 countries from September 2015 to December 2018; the final date of follow-up was December 5, 2018. Eligible patients were anthracycline-naive adults with unresectable locally advanced or metastatic STS, an Eastern Cooperative Oncology Group performance status of 0 to 1, and cardiac ejection fraction of 50% or greater.
INTERVENTIONS
Patients were randomized 1:1 to receive doxorubicin, 75 mg/m2 (day 1), combined with olaratumab (n = 258), 20 mg/kg in cycle 1 and 15 mg/kg in subsequent cycles, or placebo (n = 251) on days 1 and 8 for up to 8 21-day cycles, followed by olaratumab/placebo monotherapy.
MAIN OUTCOMES AND MEASURES
Dual primary end points were overall survival with doxorubicin plus olaratumab vs doxorubicin plus placebo in total STS and leiomyosarcoma (LMS) populations.
RESULTS
Among the 509 patients randomized (mean age, 56.9 years; 58.2% women; 46.0% with LMS), all were included in the primary analysis and had a median length of follow-up of 31 months. No statistically significant difference in overall survival was observed between the doxorubicin plus olaratumab group vs the doxorubicin plus placebo group in either population (total STS: hazard ratio, 1.05 [95% CI, 0.84-1.30], P = .69, median overall survival, 20.4 months vs 19.7 months; LMS: hazard ratio, 0.95 [95% CI, 0.69-1.31], P = .76, median overall survival, 21.6 months vs 21.9 months). Adverse events of grade 3 or greater reported in 15% or more of total patients with STS were neutropenia (46.3% vs 49.0%), leukopenia (23.3% vs 23.7%), and febrile neutropenia (17.5% vs 16.5%).
CONCLUSIONS AND RELEVANCE
In this phase 3 clinical trial of patients with advanced STS, treatment with doxorubicin plus olaratumab vs doxorubicin plus placebo resulted in no significant difference in overall survival. The findings did not confirm the overall survival benefit observed in the phase 2 trial.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02451943.
Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Doxorubicin; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Placebos; Proportional Hazards Models; Sarcoma; Survival Analysis; Young Adult
PubMed: 32259228
DOI: 10.1001/jama.2020.1707 -
Breast Cancer Research and Treatment Oct 2022Evidence of cardiotoxicity risk related to anthracycline or trastuzumab exposure is largely derived from breast cancer cohorts that under-represent socioeconomically...
PURPOSE
Evidence of cardiotoxicity risk related to anthracycline or trastuzumab exposure is largely derived from breast cancer cohorts that under-represent socioeconomically marginalized women, who may be at increased risk of cardiotoxicity because of high prevalence of cardiovascular disease risk factors. Therefore, we aimed to estimate cardiotoxicity risk among socioeconomically marginalized breast cancer patients treated with anthracyclines or trastuzumab and describe clinical consequences of cardiotoxicity.
METHODS
We linked electronic health records with institutional registry data from a Comprehensive Community Cancer Program within a safety-net health system. Eligible patients were adult females, diagnosed with first primary invasive breast cancer between 2013 and 2017, and initiated anthracyclines or trastuzumab as part of first-line therapy. We estimated cumulative incidence (risk) of cardiotoxicity with corresponding 95% confidence limits (CL) using the Aalen-Johansen estimator with death as competing risk.
RESULTS
Our study population comprised 169 women with breast cancer (103 initiated anthracyclines and 66 initiated trastuzumab). Cumulative incidence of cardiotoxicity was 21% (95% CL: 12%, 32%) at one year and 25% (95% CL: 15%, 35%) at three years among women who initiated trastuzumab, whereas cumulative incidence was 3.9% (95% CL: 1.3%, 8.9%) at one year and 5.9% (95% CL: 2.4%, 12%) at three years among women who initiated anthracyclines. More than half of patients with cardiotoxicity experienced interruption of cancer treatment.
CONCLUSION
Our findings suggest high risk of cardiotoxicity among socioeconomically marginalized breast cancer patients after initiation of anthracyclines or trastuzumab. Strategies are needed for optimizing cancer treatment effectiveness while minimizing cardiotoxicity in this population.
Topics: Adult; Anthracyclines; Antibiotics, Antineoplastic; Breast Neoplasms; Cardiotoxicity; Female; Humans; Trastuzumab
PubMed: 35971056
DOI: 10.1007/s10549-022-06695-0