TRIPASS XR تري باس

 

Abstract

Human type II topoisomerases, molecular motors that alter the DNA topology, are a major target of modern chemotherapy. Groups of catalytic inhibitors represent a new approach to overcome the known limitations of topoisomerase II poisons such as cardiotoxicity and induction of secondary tumors. Here we present a class of substituted 4,5'-bithiazoles as catalytic inhibitors targeting the human DNA topoisomerase IIα. Based on a structural comparison of the ATPase domains of human and bacterial type II topoisomerase, a focused chemical library of 4,5'-bithiazoles was assembled and screened to identify compounds that better fit the topology of the human topo IIα ATP binding site. Selected compounds showed inhibition of human topo IIα comparable or superior to that of the etoposide topo II drug, revealing a new class of inhibitors targeting this molecular motor. Further investigations showed that compounds act as catalytic inhibitors via competitive ATP inhibition. We also confirmed binding to the truncated ATPase domain of topo IIα and modeled the inhibitor molecular recognition with molecular simulations and dynophore models. The compounds also displayed promising cytotoxicity against HepG2 and MCF-7 cell lines comparable to that of etoposide. In a more detailed study with the HepG2 cell line, there was no induction of DNA double-strand breaks (DBS), and the compounds were able to reduce cell proliferation and stop the cell cycle mainly in the G1 phase. This confirms the mechanism of action of these compounds, which differs from topo II poisons also at the cellular level. Substituted 4,5'-bithiazoles appear to be a promising class for further development towards efficient and potentially safer cancer therapies exploiting the alternative topo II inhibition paradigm.

PMID: 32484690 [PubMed - as supplied by publisher]

12:25

pubmed: tutte cardiotoxicity...

Anthracycline-Induced Cardiotoxicity: Causes, Mechanisms, and Prevention.

Related Articles

Anthracycline-Induced Cardiotoxicity: Causes, Mechanisms, and Prevention.

Adv Exp Med Biol. 2020;1257:181-192

Authors: Bhagat A, Kleinerman ES

Abstract

Doxorubicin is an anthracycline and one of the more effective chemotherapy agents used in the treatment of children, adolescents, and adults with osteosarcoma. Despite its effectiveness, cardiotoxicity is a major late effect that compromises the survival and quality of life of survivors of this and other cancers. Cardiotoxicity is the inability of the heart to pump blood through the body effectively. Doxorubicin-induced cardiotoxicity is dose dependent. Additionally, the age of the patients plays a role in susceptibility with younger patients having a greater risk for cardiotoxicity and heart failure years after treatment is complete. The exact mechanism(s) responsible for doxorubicin-induced cardiotoxicity is poorly understood, and further research needs to be done to elucidate the mechanisms. This chapter summarizes the identified mechanisms that may play a role in anthracycline-induced cardiotoxicity. We will also summarize the types of cardiomyopathies that have been described in survivors treated with doxorubicin and the current recommendations for monitoring survivor for the development of cardiomyopathies. Included will be the important search for defining early biomarkers to identify patients and survivors at risk. Finally, we will summarize some of the interventions proposed for decreasing anthracycline-induced cardiotoxicity.

PMID: 32483740 [PubMed - in process]

12:25

pubmed: tutte cardiotoxicity...

Cardiotoxicity with trabectedin in the treatment of advanced soft tissue sarcoma.

//www.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--tools.ovid.com-images-wklogo.jpg Related Articles

Cardiotoxicity with trabectedin in the treatment of advanced soft tissue sarcoma.

Anticancer Drugs. 2019 01;30(1):110-115

Authors: Doherty GJ, Davidson D, Wong HH, Hatcher HM

Abstract

Trabectedin is used routinely in the palliative management of patients with advanced soft tissue sarcoma. It is not generally considered to be cardiotoxic, and there is no specific caution for its use in patients with a history of cardiac disease or risk factors. Here, we report six cases from a single academic centre where life-threatening cardiotoxicity occurred acutely during treatment with trabectedin. These patients had a median age of 72.5 years (range: 68-81) at presentation with cardiotoxicity, significantly higher than the median ages of patients treated with trabectedin in clinical trials. Cardiotoxicity occurred between cycle 1, day 10, and cycle 5, day 5 of treatment (with three events occurring during cycle 2, and one during cycle 3). Two patients had a previous cardiac history and three patients had other relevant cardiac risk factors. Five patients had been treated previously with anthracyclines. Two patients developed acute pulmonary oedema, two developed fast atrial fibrillation, one developed an ST-elevation myocardial infarction and one suffered a fatal cardiac arrest. Two had unequivocal evidence of myocardial ischaemia, and two events were acutely fatal. Trabectedin was immediately discontinued in all cases and, for the four nonfatal events, there were no recurrences of the cardiac events. As no other definitive precipitants were identified, we consider these events to be related to trabectedin toxicity. We therefore urge caution with the use of trabectedin in elderly patients, and those with a previous cardiac history, abnormal cardiac function or significant cardiac risk factors including pericardiac lesions (present in two cases reported here).

PMID: 30540596 [PubMed - indexed for MEDLINE]

4 June 2020

13:00

Cardiotoxicity News

pubmed: tutte cardiotoxicity...

Assessment of myocardial extracellular volume on body computed tomography in breast cancer patients treated with anthracyclines.

Related Articles

Assessment of myocardial extracellular volume on body computed tomography in breast cancer patients treated with anthracyclines.

Quant Imaging Med Surg. 2020 May;10(5):934-944

Authors: Monti CB, Zanardo M, Bosetti T, Alì M, De Benedictis E, Luporini A, Secchi F, Sardanelli F

Abstract

Background: Cancer treatment with anthracyclines may lead to an increased incidence of cardiac disease due to cardiotoxicity, as they may cause irreversible myocardial fibrosis. So far, the proposed methods for screening patients for cardiotoxicity have led to only limited success, while the analysis of myocardial extracellular volume (mECV) at cardiac magnetic resonance (CMR) has shown promising results, albeit requiring a dedicated exam. Recent studies have found strong correlations between mECV values obtained through computed tomography (CT), and those derived from CMR. Thus, our purpose was to evaluate the feasibility of estimating mECV on thoracic contrast-enhanced CT performed for staging or follow-up in breast cancer patients treated with anthracyclines, and, if feasible, to assess if a rise in mECV is associated with chemotherapy, and persistent over time.

Methods: After ethics committee approval, female patients with breast cancer who had undergone at least 2 staging or follow-up CT examinations at our institution, one before and one shortly after the end of chemotherapy including anthracyclines were retrospectively evaluated. Patients without available haematocrit, with artefacts in CT images, or who had undergone radiation therapy of the left breast were excluded. Follow-up CT examinations at longer time intervals were also analysed, when available. mECV was calculated on scans obtained at 1, and 7 min after contrast injection.

Results: Thirty-two female patients (aged 57±13 years) with pre-treatment haematocrit 38%±4%, and ejection fraction 64%±6% were analysed. Pre-treatment mECV was 27.0%±2.9% at 1 min, and 26.4%±3.8% at 7 min, similar to values reported for normal subjects in the literature. Post-treatment mECV (median interval: 89 days after treatment) was 31.1%±4.9%, and 30.0%±5.1%, respectively, values significantly higher than pre-treatment values at all times (P<0.005).0.548) when compared to post-treatment values.

Conclusions: mECV values from contrast-enhanced CT scans could play a role in the assessment of myocardial condition in breast cancer patients undergoing anthracycline-based chemotherapy. CT-derived ECV could be an imaging biomarker for the monitoring of therapy-related cardiotoxicity, allowing for potential secondary prevention of cardiac damage, using data derived from an examination that could be already part of patients' clinical workflow.

PMID: 32489918 [PubMed]

5 June 2020

13:41

Cardiotoxicity News

pubmed: tutte cardiotoxicity...

Cardiotoxicity of cancer therapy and current research efforts.

Related Articles

Cardiotoxicity of cancer therapy and current research efforts.

Br J Community Nurs. 2020 Jun 02;25(6):308

Authors: Mendes A

PMID: 32496853 [PubMed - as supplied by publisher]

13:41

pubmed: tutte cardiotoxicity...

[Cardiotoxicity of immune checkpoint inhibitors used in cancer treatment].

Related Articles

[Cardiotoxicity of immune checkpoint inhibitors used in cancer treatment].

Rev Med Suisse. 2020 Jun 03;16(696):1165-1168

Authors: Arangalage D, Pavon AG, Hugelshofer S, Desgraz B, Tzimas G, Delyon J, Muller O, Obeid M, Ribi C, Michielin O, Özdemir BC, Monney P

Abstract

Immune checkpoint inhibitors (ICI) have revolutionized the field of oncology, by reshaping the prognosis of many cancers and are progressively becoming the standard of care. One of the costs of these advances is the emergence of a new spectrum of immune-related adverse events (irAEs), of which cardiovascular irAEs are particularly feared. ICI-induced myocarditis is often a diagnostic challenge because of the vast heterogeneity of clinical presentations, and it is associated with a high mortality rate of around 50%. The present article summarizes the cardiac manifestations, the diagnostic strategy and the therapeutic management of patients with ICI-induced myocarditis used in the treatment of cancer.

PMID: 32496706 [PubMed - as supplied by publisher]

13:41

pubmed: tutte cardiotoxicity...

Electrocardiographic Changes Associated With Ibrutinib Exposure.

Related Articles

Electrocardiographic Changes Associated With Ibrutinib Exposure.

Cancer Control. 2020 Jan-Dec;27(1):1073274820931808

Authors: Fradley MG, Welter-Frost A, Gliksman M, Emole J, Viganego F, Lee DH, Shah B, Chavez JC, Pinilla-Ibarz J, Schabath MB

Abstract

Although ibrutinib-associated atrial and ventricular arrhythmias have been well described, there is little information about ibrutinib's effects on other electrocardiographic parameters, particularly the QT interval. Using our database of 137 patients treated with ibrutinib, we retrospectively identified 21 patients in whom an electrocardiogram (ECG) was obtained both prior to and after ibrutinib exposure. All traditional ECG parameters as well as QT dispersion were manually measured by an electrophysiologist. Compared to baseline ECGs, post ibrutinib ECGs demonstrated QT interval shortening from 386 ms to 356 ms (P = .007), corrected QT interval shortening using Bazett's formula from 446 ms to 437 ms (P = .04), and corrected QT interval shortening using Fridericia's formula from 425 ms to 407 ms (P = .003). QT dispersion also increased post ibrutinib exposure compared to baseline (39.8 ms vs 57.3 ms, P = .002). There was no significant change in other ECG parameters. In conclusion, both the absolute and corrected QT intervals significantly shortened after ibrutinib exposure, while there was a significant increase in QT dispersion. These findings may point to a common underlying electrophysiologic mechanism of ibrutinib-associated arrhythmias.

PMID: 32496158 [PubMed - as supplied by publisher]

13:41

pubmed: tutte cardiotoxicity...

A Case of Reversible Cancer Therapeutics-related Cardiac Dysfunction Complicating Intra-cardiac Thrombi.

Related Articles

A Case of Reversible Cancer Therapeutics-related Cardiac Dysfunction Complicating Intra-cardiac Thrombi.

Intern Med. 2020 Jun 02;:

Authors: Tsujinaga S, Iwano H, Oshino T, Kadosaka T, Mizuguchi Y, Motoi K, Chiba Y, Koya T, Temma T, Kamiya K, Fukushima A, Koizumi T, Sato T, Takenaka S, Tada A, Ishizaka S, Sarashina M, Omote K, Kamada R, Konishi T, Sato T, Nagai T, Yamashita H, Anzai T

Abstract

Epirubicin-based chemotherapy carries a risk of inducing heart failure, although the frequency is rare. Bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, has recently been widely used in patients with recurrent breast cancer as a first-line chemotherapeutic agent. Heart failure or arterial thromboembolism has been reported as a rare cardiovascular complication of bevacizumab. We herein report a breast cancer patient with reversible cancer therapeutics-related cardiac dysfunction associated with bevacizumab and epirubicin complicating intracardiac thrombi in the left atrium and left ventricle. This case underscores the importance of tailored medical planning according to the individual status in patients receiving anti-cancer therapies.

PMID: 32493855 [PubMed - as supplied by publisher]

13:41

pubmed: tutte cardiotoxicity...

Cardiotoxicity evaluation using magnetic resonance imaging in breast Cancer patients (CareBest): study protocol for a prospective trial.

Related Articles

Cardiotoxicity evaluation using magnetic resonance imaging in breast Cancer patients (CareBest): study protocol for a prospective trial.

BMC Cardiovasc Disord. 2020 Jun 03;20(1):264

Authors: Hong YJ, Kim GM, Han K, Kim PK, Lee SA, An E, Lee JY, Lee HJ, Hur J, Kim YJ, Kim MJ, Choi BW

Abstract

BACKGROUND: Cardiovascular disease is second only to cancer recurrence as a determinant of lifespan in cancer survivors, and cancer therapy-related cardiac dysfunction is a clinically important risk factor. We aim to investigate the use of cardiac magnetic resonance imaging (MRI) to evaluate early tissue changes and perform functional assessment of chemo- and radiation-induced cardiotoxicity and to identify MRI prognostic indicators of cardiotoxicity in breast cancer patients.

METHODS: A 3-min cardiac imaging protocol will be added to the breast MRI examination to diagnose cardiotoxicity in breast cancer patients. Standardized MRI-based evaluation of breast cancer and the left ventricular myocardium will be performed at baseline and at 3, 6, and 12 months and 2 years or more after cancer treatment. We will analyze both ventricular volume and ejection fraction (EF), strain of left ventricle (LV), native T1, extracellular volume fraction (ECV), and T2 values acquired in the mid LV.

DISCUSSION: The primary result of this study will be the comparison of the prognostic value of MRI parameters (native T1, ECV, both ventricular systolic function and LV strain) for cardiotoxicity. The endpoint is defined as the occurrence of a major adverse cardiac event (MACE). The secondary outcome will be an assessment of the temporal relationships between contractile dysfunction and microstructural injury over 4 years using MRI. This study will assess the usefulness of quantitative MRI to diagnose cardiotoxicity and will clarify the temporal relationships between contractile dysfunction and microstructural injury of the LV myocardium using MRI during breast cancer treatment.

TRIAL REGISTRATION: The protocol was registered at clinicaltrials.gov (Clinical trial no. NCT03301389) on October 4, 2017.

PMID: 32493217 [PubMed - in process]

13:41

pubmed: tutte cardiotoxicity...

The COVID-19 Pandemic and its Impact on the Cardio-Oncology Population.

//www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--production.springer.de-OnlineResources-Logos-springerlink.gif //www.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--www.ncbi.nlm.nih.gov-corehtml-pmc-pmcgifs-pubmed-pmc.png Related Articles

The COVID-19 Pandemic and its Impact on the Cardio-Oncology Population.

Curr Oncol Rep. 2020 05 28;22(6):60

Authors: Asokan I, Rabadia SV, Yang EH

Abstract

PURPOSE OF REVIEW: The novel Coronavirus (2019-nCoV, COVID-19) is historically one of the most severe acute respiratory syndromes and pandemics to affect the globe in the twenty-first century. Originating in Wuhan, the virus rapidly spread and impacted subsets of populations with initial unclear risk factors contributing to worsening morbidity and mortality. Patients with diagnosis of cancer and undergoing treatment further represent a population at risk for worsening cardiopulmonary outcomes. This review explores specific risk factors, diagnoses, and treatment options that impact cardio-oncologic patients with COVID-19.

RECENT FINDINGS: Multiple studies globally, including Italy, China, and the USA, have documented severe outcomes. Cancer patients are at increased risk of cardiac injury which itself is a risk factor for mortality. Additionally, elderly cancer patients undergoing recent anti-cancer treatment may be at greater risk for sustaining worse outcomes, although data remains suboptimal in this population. Major gaps remain regarding risk associated with type of cancer and type of anti-cancer treatment, as well as the layered risk of cardiovascular disease and cancer. Immunomodulatory therapies used to treat cytokine release syndrome secondary to anti-cancer therapies, as well as other agents being traditionally used to treat cardiovascular and cancer disease states, are being investigated for treatment of COVID-19. Hypertension, cardiovascular disease, diabetes, and cancer have been associated with more severe COVID-19 infection and worse outcomes. Patients undergoing anti-cancer therapy or those who have suffered from coronavirus infection may develop long-standing changes, not limited to pulmonary fibrosis, hyperlipidemia, and worsening atherosclerosis. Those undergoing anti-cancer therapy are at theoretically increased susceptibility for infection, with type of cancer not necessarily dictating outcome. A review of the literature of patients with cardiovascular and/or cancer disease is presented, as well as proposed strategies to attenuate risk regarding treatment, management, and surveillance in this vulnerable population.

PMID: 32462289 [PubMed - indexed for MEDLINE]

13:41

pubmed: tutte cardiotoxicity...

Cardiotoxicity evaluation in pediatric patients with acute lymphoblastic leukemia - results of prospective study.

Related Articles

Cardiotoxicity evaluation in pediatric patients with acute lymphoblastic leukemia - results of prospective study.

Med Ultrason. 2019 Nov 24;21(4):449-455

Authors: Radu LE, Ghiorghiu I, Oprescu A, Dorobantu D, Arion C, Colita A

Abstract

AIM: The chemotherapy protocol for acute lymphoblastic leukemia (ALL) uses low doses of anthracyclines (AC), generally associated with subclinical cardiotoxicity. The aim of our study was to evaluate the serum biomarkers and echocardiography parameters in children with ALL treated with AC in order to determine the most useful element for early detection of cardiotoxicity.

MATERIAL AND METHODS: In this prospective study, troponin I (TnI) and heart-type fatty acid binding protein (HFABP) were assessed five times during the first year after the onset of ALL. Serial Tissue Doppler Imaging and conventional cardiac echography were performed by two pediatric cardiologists (intraclass correlation coefficient over 0.85 for all measurements) in three periods during the study protocol.

RESULTS: We evaluated 48 children with ALL. TnI increased during therapy, without returning to baseline values one year after diagnosis. HFABP did not show significant changes during the study protocol. Left ventricle outflow tract time-velocity integral and peak systolic septal mitral annulus velocity decreased during chemotherapy and returned to baseline levels at one year after diagnosis, while peak systolic tricuspid annulus velocity and excursion, maintained a descending tendency. Early filling transmitral flow velocity and E/A ratio were also transiently influenced by chemotherapy.

CONCLUSIONS: The study showed signs of transient cardiotoxicity in the left ventricle and diastolic parameters after chemotherapy, compared to right ventricle parameters which maintained low values even one year after diagnosis. TnI proved to be directly proportional to chemotherapy doses but HFABP was not useful in this setting.

PMID: 31765454 [PubMed - indexed for MEDLINE]

6 June 2020

14:16

Cardiotoxicity News

pubmed: tutte cardiotoxicity...

3D-STI evaluation of the effect of dexrazoxane on the mechanical properties of right ventricular myocardium in breast cancer patients treated with pirarubicin.

Related Articles

3D-STI evaluation of the effect of dexrazoxane on the mechanical properties of right ventricular myocardium in breast cancer patients treated with pirarubicin.

Ann Palliat Med. 2020 May;9(3):1187-1197

Authors: Wang Y, Lu C, Li H, Liu K, Yu M, Zhang P