scholarly journals Targeted anti-BCR-ABL+ ALL therapy may benefit the heart

2021 ◽  
Author(s):  
Hanna Kirchhoff ◽  
Melanie Ricke-Hoch ◽  
Katharina Wohlan ◽  
Stefan Pietzsch ◽  
Uemran Karsli ◽  
...  
Keyword(s):  
Side Effects ◽  
Genetic Model ◽  
Lymphoblastic Leukemia ◽  
Cost Benefit ◽  
Left Ventricular ◽  
Cardiac Damage ◽  
Cardiac Recovery ◽  
Cardiac Atrophy ◽  
Anti Cancer ◽  
Organ Specific

Targeted therapies are currently considered the best cost-benefit anti-cancer treatment. In hematological malignancies, however, relapse rates and non-hematopoietic side effects including cardiotoxicity remain high. We here describe significant heart damage due to advanced acute lymphoblastic leukemia with t(9;22) encoding the bcr-abl oncogene (BCR-ABL+ ALL) in murine xenotransplantation models. Echocardiography reveals severe cardiac dysfunction with impaired left ventricular function and reduced heart and cardiomyocyte dimensions associated with increased apoptosis. This cardiac damage is fully reversible, but cardiac recovery depends on the therapy used to induce ALL remission. Chemotherapy-free therapy with dasatinib and venetoclax (targeting the BCR-ABL oncoprotein and mitochondrial Bcl2, respectively), as well as dexamethasone can fully revert cardiac defects whereas depletion of otherwise identical ALL in a genetic model using HSV-TK cannot. Mechanistically, dexamethasone induces pro-apoptotic BIM expression and apoptosis in ALL cells but enhances pro-survival BCLXL expression in cardiomyocytes and clinical recovery with reversion of cardiac atrophy. These data demonstrate that therapies designed to optimize apoptosis induction in ALL may circumvent cardiac on-target side effects and may even activate cardiac recovery. In the future, combining careful clinical monitoring of cardiotoxicity in leukemic patients with further characterization of organ-specific side effects and signaling pathways activated by malignancy and/or anti-tumor therapies seems reasonable.

Nitrogen Mustards as Alkylating Agents: A Review on Chemistry, Mechanism of Action and Current USFDA Status of Drugs

2019 ◽  
Vol 19 (9) ◽  
pp. 1080-1102 ◽  
Author(s):  
Ghansham S. More ◽  
Asha B. Thomas ◽  
Sohan S. Chitlange ◽  
Rabindra K. Nanda ◽  
Rahul L. Gajbhiye
Keyword(s):  
Side Effects ◽  
Mechanism Of Action ◽  
Anticancer Agents ◽  
Nitrogen Mustard ◽  
Alkylating Agents ◽  
Cross Linking ◽  
Nitrogen Mustards ◽  
Information Leaflets ◽  
Anti Cancer ◽  
Approved Drugs

Background & Objective: :Nitrogen mustard derivatives form one of the major classes of anti-cancer agents in USFDA approved drugs list. These are polyfunctional alkylating agents which are distinguished by a unique mechanism of adduct formation with DNA involving cross-linking between guanine N-7 of one strand of DNA with the other. The generated cross-linking is irreversible and leads to cell apoptosis. Hence it is of great interest to explore this class of anticancer alkylating agents.Methods::An exhaustive list of reviews, research articles, patents, books, patient information leaflets, and orange book is presented and the contents related to nitrogen mustard anti-cancer agents have been reviewed. Attempts are made to present synthesis schemes in a simplified manner. The mechanism of action of the drugs and their side effects are also systematically elaborated.Results::This review provides a platform for understanding all aspects of such drugs right from synthesis to their mechanism of action and side effects, and lists USFDA approved ANDA players among alkylating anticancer agents in the current market.Conclusion: :Perusing this article, generic scientists will be able to access literature information in this domain easily to gain insight into the nitrogen mustard alkylating agents for further ANDA development. It will help the scientific and research community to continue their pursuit for the design of newer and novel heterocyclic alkylating agents of this class in the coming future.

Encapsulation of Imatinib in Targeted KIT-5 Nanoparticles for Reducing its Cardiotoxicity and Hepatotoxicity

2020 ◽  
Vol 20 (16) ◽  
pp. 1966-1980
Author(s):  
Jaleh Varshosaz ◽  
Saeedeh Fardshouraki ◽  
Mina Mirian ◽  
Leila Safaeian ◽  
Setareh Jandaghian ◽  
...  
Keyword(s):  
Controlled Release ◽  
Side Effects ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Drug Carrier ◽  
Free Drug ◽  
Jurkat Cells ◽  
Targeted Nanoparticles ◽  
Inhibitor Drug ◽  
Histopathological Results

Background: Using imatinib, a tyrosine kinase inhibitor drug used in lymphoblastic leukemia, has always had limitations due to its cardiotoxicity and hepatotoxicity side effects. The objective of this study is to develop a target-oriented drug carrier to minimize these adverse effects by the controlled release of the drug. Methods: KIT-5 nanoparticles were functionalized with 3-aminopropyltriethoxysilane and conjugated to rituximab as the targeting agent for the CD20 positive receptors of the B-cells. Then they were loaded with imatinib and their physical properties were characterized. The cell cytotoxicity of the nanoparticles was studied by MTT assay in Ramos (CD20 positive) and Jurkat cell lines (CD20 negative) and their cellular uptake was shown by fluorescence microscope. Wistar rats received an intraperitoneal injection of 50 mg/kg of the free drug or targeted nanoparticles for 21 days. Then the level of aspartate Aminotransferase (AST), alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP) and Lactate Dehydrogenase (LDH) were measured in serum of animals. The cardiotoxicity and hepatotoxicity of the drug were also studied by hematoxylin and eosin staining of the tissues. Results: The targeted nanoparticles of imatinib showed to be more cytotoxic to Ramos cells rather than Jurkat cells. The results of the biochemical analysis displayed a significant reduction in AST, ALT, ALP, and LDH levels in animals treated with targeted nanoparticles, compared to the free drug group. By comparison with the free imatinib, histopathological results represented less cardiotoxicity and hepatotoxicity in the animals, which received the drug through the current designed delivery system. Conclusion: The obtained results confirmed that the rituximab targeted KIT-5 nanoparticles are promising in the controlled release of imatinib and could decrease its cardiotoxicity and hepatotoxicity side effects.

Novel staging classification of primary mitral regurgitation based on the presence of cardiac damage

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A.L Van Wijngaarden ◽  
Y.L Hiemstra ◽  
P Van Der Bijl ◽  
V Delgado ◽  
N Ajmone Marsan ◽  
...  
Keyword(s):  
Mitral Regurgitation ◽  
Kidney Function ◽  
Left Ventricular ◽  
Prognostic Impact ◽  
Cardiac Damage ◽  
Stage 4 ◽  
All Cause Mortality ◽  
Primary Mitral Regurgitation ◽  
Stage 1 ◽  
Staging Classification

Abstract Background The indication for surgery in patients with severe primary mitral regurgitation (MR) is currently based on the presence of symptoms, left ventricular (LV) dilatation and dysfunction, atrial fibrillation and pulmonary hypertension. The aim of this study was to evaluate the prognostic impact of a new staging classification based on cardiac damage including the known risk factors but also including global longitudinal strain (GLS), severe left atrial (LA) dilatation and right ventricular (RV) dysfunction. Methods In total 614 patients who underwent surgery for severe primary MR with available baseline transthoracic echocardiograms were included. Patients were classified according to the extent of cardiac damage (Figure): Stage 0-no cardiac damage, Stage 1-LV damage, Stage 2-LA damage, Stage 3-pulmonary vasculature or tricuspid valve damage and Stage 4-RV damage. Patients were followed for all-cause mortality. Results Based on the proposed classification, 172 (28%) patients were classified as Stage 0, 102 (17%) as Stage 1, 134 (21%) as Stage 2, 135 (22%) as Stage 3 and 71 (11%) as Stage 4. The more advanced the stage, the older the patients were with worse kidney function, more symptoms and higher EuroScore. Kaplan-Meier curve analysis revealed that patients with more advanced stages of cardiac damage had a significantly worse survival (log-rank chi-square 35.2; p<0.001) (Figure). On multivariable analysis, age, male, chronic obstructive pulmonary disease, kidney function, and stage of cardiac damage were independently associated with all-cause mortality. For each stage increase, a 22% higher risk for all-cause mortality was observed (95% CI: 1.064–1.395; p=0.004). Conclusion In patients with severe primary MR, a novel staging classification based on the extent of cardiac damage, may help refining risk stratification, particularly including also GLS, LA dilatation and RV dysfunction in the assessment. Funding Acknowledgement Type of funding source: None

scholarly journals ECG Scoring for the Evaluation of Therapy-Naïve Cancer Patients to Predict Cardiotoxicity

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1197
Author(s):  
Julia Pohl ◽  
Raluca-Ileana Mincu ◽  
Simone M. Mrotzek ◽  
Reza Wakili ◽  
Amir A. Mahabadi ◽  
...  
Keyword(s):  
High Risk ◽  
Cancer Patients ◽  
Left Ventricular ◽  
Cardiac Biomarkers ◽  
Cancer Therapies ◽  
University Hospitals ◽  
Anti Cancer ◽  
Risk Patients ◽  
Qrs Duration ◽  
Ecg Score

Objective: To evaluate a new electrocardiographic (ECG) score reflecting domains of electrical and structural alterations in therapy-naïve cancer patients to assess their risk of cardiotoxicity. Methods: We performed a retrospective analysis of 134 therapy-naïve consecutive cancer patients in our two university hospitals concerning four ECG score parameters: Contiguous Q-waves, markers of left ventricular (LV) hypertrophy, QRS duration and JTc prolongation. Cardiotoxicity was assessed after a short-term follow-up (up to 12 months). Results: Of all the patients (n = 25), 19% reached 0 points, 50% (n = 67) reached 1 point, 25% (n = 33) reached 2 points, 5% (n = 7) reached 3 points and 0.7% reached 4 or 5 points (n = 1 respectively). The incidence of cardiotoxicity (n = 28 [21%]) increased with the ECG score, with 0 points at 0%, 1 point 7.5%, 2 points 55%, 3 points 71% and ≥3 points 50%. In the ROC (Receiver operating curves) analysis, the best cut-off for predicting cardiotoxicity was an ECG score of ≥2 points (sensitivity 82%, specificity 82%, AUC 0.84, 95% CI 0.77–0.92, p < 0.0001) which was then defined as a high-risk score. High-risk patients did not differ concerning their age, LV ejection fraction, classical cardiovascular risk factors or cardiac biomarkers compared to those with a low-risk ECG score. Conclusion: ECG scoring prior to the start of anti-cancer therapies may help to identify therapy-naïve cancer patients at a higher risk for the development of cardiotoxicity.

scholarly journals Speckle tracking echocardiography in primary mitral regurgitation: should we reconsider the time for intervention?

2021 ◽  
Author(s):  
Maria Concetta Pastore ◽  
Giulia Elena Mandoli ◽  
Aleksander Dokollari ◽  
Gianluigi Bisleri ◽  
Flavio D’Ascenzi ◽  
...  
Keyword(s):  
Mitral Regurgitation ◽  
Right Ventricular ◽  
Speckle Tracking ◽  
Speckle Tracking Echocardiography ◽  
Right Ventricular Dysfunction ◽  
Left Ventricular ◽  
Main Concern ◽  
Cardiac Damage ◽  
Asymptomatic Patients ◽  
Right Ventricular Strain

Abstract Thanks to the improvement in mitral regurgitation (MR) diagnostic and therapeutic management, with the introduction of minimally invasive techniques which have considerably reduced the individual surgical risk, the optimization of the timing for MR “open” or percutaneous surgical treatment has become a main concern which has highly raised scientific interest. In fact, the current indications for intervention in MR, especially in asymptomatic patients, rely on echocardiographic criteria with high severity cut-offs that are fulfilled only when not only mitral valve apparatus but also the cardiac chambers’ structure and function are severely impaired, which results in poor benefits for post-operative clinical outcome. This led to the need of new indices to redefine the optimal surgical timing in these patients. Speckle tracking echocardiography provides early markers of cardiac dysfunction due to subtle myocardial impairment; therefore, it could offer pivotal information in this setting. In fact, left ventricular and left atrial strains have already shown evidence about their usefulness in recognizing MR impact not only on symptoms and quality of life but also on cardiovascular events and new-onset atrial fibrillation in these patients. Moreover, right ventricular strain could be used to identify those patients with advanced cardiac damage and different grades of right ventricular dysfunction, which entails higher risks for cardiac surgery that could overweigh surgical benefits. This review aims to describe the importance of reconsidering the timing of intervention in MR and to analyze the potential additive value of speckle tracking echocardiography in this clinical setting.

Very early detection of low dose anti-cancer therapy-related cardiotoxicity in lymphoma patients

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Y.W Liu ◽  
H.Y Chang ◽  
C.H Lee ◽  
W.C Tsai ◽  
P.Y Liu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cancer Therapy ◽  
Cardiac Dysfunction ◽  
Systolic Dysfunction ◽  
Multivariable Analysis ◽  
Cardiopulmonary Exercise Test ◽  
Left Ventricular ◽  
Funding Source ◽  
Anti Cancer ◽  
All Cause Mortality

Abstract Background and purpose Left ventricular (LV) global peak systolic longitudinal strain (GLS) by speckle-tracking echocardiography is a sensitive modality for the detection of subclinical LV systolic dysfunction and a powerful prognostic predictor. However, the clinical implication of LV GLS in lymphoma patients receiving anti-cancer therapy remains unknown. Methods We prospectively enrolled 74 patients (57.9±17.0 years old, 57% male) with lymphoma who underwent echocardiography prior to chemotherapy, post 3rd and 6th cycle and 1 year after chemotherapy. Cancer therapy-related cardiac dysfunction (CTRCD) is defined as the reduction of absolute GLS value from baseline of ≥15%. All the eligible patients underwent a cardiopulmonary exercise test (CPET) upon completion of 3 cycles of anti-cancer therapy. The primary outcome was defined as a composite of all-cause mortality and heart failure events. Results Among 36 (49%) patients with CTRCD, LV GLS was significantly decreased after the 3rd cycle of chemotherapy (20.1±2.6% vs. 17.5±2.3%, p&lt;0.001). In the multivariable analysis, male sex and anemia (hemoglobin &lt;11 g/dL) were found to be independent risk factors of CTRCD. Objectively, patients with CTRCD had lower minute oxygen consumption/kg (VO2/kg) and lower VO2/kg value at anaerobic threshold in the CPET. The incidence of the primary composite outcome was higher in the CTRCD group than in the non-CTRCD group (hazard ratio 3.21; 95% CI, 1.04–9.97; p=0.03). Conclusion LV GLS is capable of detecting early cardiac dysfunction in lymphoma patients receiving anti-cancer therapy. Patients with CTRCD not only had a reduced exercise capacity but also a higher risk of all-cause mortality and heart failure events. Change of LVEF and GLS after cancer Tx Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The Ministry of Science and Technology (MOST), Taiwan

scholarly journals Molecular Changes Underlying Genistein Treatment of Wound Healing: A Review

2021 ◽  
Vol 43 (1) ◽  
pp. 127-141
Author(s):  
Matúš Čoma ◽  
Veronika Lachová ◽  
Petra Mitrengová ◽  
Peter Gál
Keyword(s):  
Wound Healing ◽  
Side Effects ◽  
Biologically Active ◽  
Estrogen Receptor Modulators ◽  
Age Related ◽  
Skin Repair ◽  
Genistein Treatment ◽  
Anti Cancer ◽  
Major Factors ◽  
Promising Source

Estrogen deprivation is one of the major factors responsible for many age-related processes including poor wound healing in postmenopausal women. However, the reported side-effects of estrogen replacement therapy (ERT) have precluded broad clinical administration. Therefore, selective estrogen receptor modulators (SERMs) have been developed to overcome the detrimental side effects of ERT on breast and/or uterine tissues. The use of natural products isolated from plants (e.g., soy) may represent a promising source of biologically active compounds (e.g., genistein) as efficient alternatives to conventional treatment. Genistein as natural SERM has the unique ability to selectively act as agonist or antagonist in a tissue-specific manner, i.e., it improves skin repair and simultaneously exerts anti-cancer and chemopreventive properties. Hence, we present here a wound healing phases-based review of the most studied naturally occurring SERM.

Probiotics for the Chemoprotective Role Against the Toxic Effect of Cancer Chemotherapy

2021 ◽  
Vol 21 ◽  
Author(s):  
Aafrin Waziri ◽  
Charu Bharti ◽  
Mohammed Aslam ◽  
Parween Jamil ◽  
Aamir Mirza ◽  
...  
Keyword(s):  
Side Effects ◽  
Clinical Management ◽  
Clinical Evidence ◽  
Unmet Need ◽  
Chemotherapeutic Agents ◽  
Antitumor Effects ◽  
Anti Cancer ◽  
Different Types ◽  
Growth Promoting ◽  
High Degree

Background: The processes of chemo- and radiation therapy-based clinical management of different types of cancers are associated with toxicity and side effects of chemotherapeutic agents. So, there is always an unmet need to explore agents to reduce such risk factors. Among these, natural products have generated much attention because of their potent antioxidant and antitumor effects. In the past, some breakthrough outcomes established that various bacteria in the human intestinal gut are bearing growth-promoting attributes and suppressing the conversion of pro-carcinogens into carcinogens. Hence, probiotics integrated approaches are nowadays being explored as rationalized therapeutics in the clinical management of cancer. Methods: Here, published literature was explored to review chemoprotective roles of probiotics against toxic and side effects of chemotherapeutics. Results: Apart from excellent anti-cancer abilities, probiotics are bearing and alleviate toxicity and side effects of chemotherapeutics, with a high degree of safety and efficiency. Conclusion: Preclinical and clinical evidence suggested that due to the chemoprotective roles of probiotics against side effects and toxicity of chemotherapeutics, their integration in chemotherapy would be a judicious approach.

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