ABSTRACT

Quinalizarin, an analogue of anthracycline anticancer agents, is an anticancer agent itself. A CuII complex was prepared and characterized by elemental analysis, UV-Vis & IR spectroscopy, mass spectrometry, EPR and DFT. The intention behind the preparation of the complex was to increase cellular uptake, compare its binding with DNA against that of quinalizarin, modulation of semiquinone formation, realization of human DNA topoisomerase I & human DNA topoisomerase II inhibition and observation of anticancer activity. While the first two attributes of complex formation lead to increased efficacy, decrease in semiquinone generation could results in a compromise with efficacy. Inhibition of human DNA topoisomerase makes up this envisaged compromise in free radical activity since the complex shows remarkable ability to disrupt activities of human DNA topoisomerase I and II. The complex unlike quinalizarin, does not catalyze flow of electrons from NADH to O2 to the extent known for quinalizarin. Hence, decrease in semiquinone or superoxide radical anion could make modified quinalizarin [as CuII complex] less efficient in free radical pathway. However, it would be less cardiotoxic and that would be advantageous to qualify it as a better anticancer agent. Although binding to calf thymus DNA was comparable to quinalizarin, it was weaker than anthracyclines. Low cost of quinalizarin could justify consideration as a substitute for anthracyclines but the study revealed IC50 of quinalizarin/CuII-quinalizarin was much higher than anthracyclines or their complexes. Even then, there is a possibility that CuII-quinalizarin could be an improved and less costly form of quinalizarin as anticancer agent.

PMID:37776829 | DOI:10.1016/j.jinorgbio.2023.112369

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PubMed articles on: Cardio-Oncology

The Effects of Drug Exposure and SNPs on Aaptinib-induced Severe Toxicities in Solid Tumors

Drug Metab Dispos. 2023 Sep 29:DMD-AR-2023-001428. doi: 10.1124/dmd.123.001428. Online ahead of print.

ABSTRACT

PURPOSE: To investigate the value of drug exposure and host germline genetic factors in predicting apatinib (APA)-related toxicities.

METHOD: In this prospective study, plasma APA concentrations were quantified using liquid chromatography with tandem mass spectrometry, and 57 germline mutations were genotyped in 126 advanced solid tumor patients receiving 250mg daily APA, a vascular endothelial growth factor receptor II inhibitor. The correlation between drug exposure, genetic factors, and the toxicity profile was analyzed.

RESULTS: Non-small cell lung cancer (NSCLC) was more prone to APA-related toxicities and plasma concentrations of APA and its main metabolite M1-1 could be associated with high-grade adverse events (AEs) (P＜0.01; M1-1: P＜0.01) and high-grade anti-angiogenetic toxicities (APA: P = 0.034; P＜0.05), including hypertension, proteinuria and hand-foot syndrome, in the subgroup of NSCLC. Besides, CYP2C9 rs34532201 TT carriers tended to have higher levels of APA (P＜0.001) and M1-1 (P＜0.01) while CYP2C9 rs1936968 GG carriers were predisposed to higher levels of M1-1 (P＜0.01).

CONCLUSION: Plasma APA and M1-1 exposures were able to predict severe AEs in NSCLC patients. Dose optimization and drug exposure monitoring might need considering in NSCLC patients with CYP2C9 rs34532201 TT and rs1936968 GG. Significance Statement Apatinib is an anti-VEGFR2 inhibitor for the treatment of multiple cancers. Though substantial in response, apatinib-induced toxicity has been a critical issue that is worth clinical surveillance. Few data on the role of drug exposure and genetic factors in apatinib-induced toxicity are available. Our study demonstrated a distinct drug-exposure relationship in NSCLC but not other tumors and provided invaluable evidence of drug exposure levels and single nucleotide polymorphisms as predictive biomarkers in apatinib-induced severe toxicities.

PMID:37775332 | DOI:10.1124/dmd.123.001428

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PubMed articles on: Cancer & VTE/PE

The Role of Mechanical Thrombectomy for Acute Massive Pulmonary Embolism in a Patient With Unilateral Lung Transplant and Atrial Septal Defect

J Endovasc Ther. 2023 Sep 30:15266028231201357. doi: 10.1177/15266028231201357. Online ahead of print.

ABSTRACT

PURPOSE: The risk of thromboembolic disease is high in patients with lung transplantation and is associated with significant morbidity and mortality with single healthy transplanted lung. We present a case involving successful endovascular management of life-threatening acute massive pulmonary embolism (PE) in a patient with single lung transplant and atrial septal defect (ASD).

CASE REPORT: A 65-year-old man with a history of interstitial lung disease status post single left orthotopic lung transplant in 2012 presented with acute massive PE and clot burden in the pulmonary arteries of the transplanted left lung. Severe right heart dysfunction, hemodynamic instability, and requirement for vasopressors persisted post systemic thrombolytic therapy. As a result, the patient underwent successful endovascular mechanical thrombectomy with immediate improvement in oxygen saturation and hemodynamic status. The procedure was performed without adverse outcomes or paradoxical embolization despite the presence of ASD. The right heart dysfunction resolved, the patient was extubated the next day, and was discharged to home 2 days post procedure.

CONCLUSIONS: Endovascular mechanical thrombectomy was safely used to treat acute massive PE in a single transplanted lung in the presence of ASD.

CLINICAL IMPACT: Endovascular mechanical thrombectomy could be safely utilized to treat patients with lung transplant and acute massive or submassive pulmonary embolism. However, safely of mechanical thrombectomy should be determined in case-based scenarios and based on time interval from transplantation to when the thrombectomy is required.

PMID:37776207 | DOI:10.1177/15266028231201357

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PubMed articles on: Cardio-Oncology

Reverse cardio-oncology: A budding concept

Indian Heart J. 2023 Sep 27:S0019-4832(23)00163-3. doi: 10.1016/j.ihj.2023.09.004. Online ahead of print.

ABSTRACT

Having established the significance of cardiovascular side-effects of anti-neoplastic drugs, present day cardio-oncology has forayed into newer territories buoyed by research into the multiple connections that exist between cardiovascular disease and cancer. An emerging concept of reverse cardio-oncology focuses on the heightened risk of cancer in patients with cardiovascular disease. Common mechanistics of cancer and heart failure (HF) like chronic inflammation and clonal haematopoesis as well as common predisposing factors like obesity and diabetes underline the relation between both cardiovascular disease and various cancers.This review discusses the potential magnitude of the problem, the underlying pathophysiological mechanisms and classification of this novel subject.

PMID:37774949 | DOI:10.1016/j.ihj.2023.09.004

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PubMed articles on: Cancer & VTE/PE

Real-world data emulating randomized controlled trials of non-vitamin K antagonist oral anticoagulants in patients with venous thromboembolism

BMC Med. 2023 Sep 29;21(1):375. doi: 10.1186/s12916-023-03069-1.

ABSTRACT

BACKGROUND: Emulating randomized controlled trials (RCTs) by real-world evidence (RWE) studies would benefit future clinical and regulatory decision-making by balancing the limitations of RCT. We aimed to evaluate whether the findings from RWE studies can support regulatory decisions derived from RCTs of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with venous thromboembolism (VTE).

METHODS: Five landmark trials (AMPLIFY, RE-COVER II, Hokusai-VTE, EINSTEIN-DVT, and EINSTEIN-PE) of NOACs were emulated using the South Korean nationwide claims database (January 2012 to August 2020). We applied an active comparator and new-user design to include patients who initiated oral anticoagulants within 28 days from their VTE diagnoses. The prespecified eligibility criteria, exposure (each NOAC, such as apixaban, rivaroxaban, dabigatran, and edoxaban), comparator (conventional therapy, defined as subcutaneous heparin followed by warfarin), and the definition of outcomes from RCTs were emulated as closely as possible in each separate emulation cohort. The primary outcome was identical to each trial, which was defined as recurrent VTE or VTE-related death. The safety outcome was major bleeding. Propensity score matching was conducted to balance 69 covariates between the exposure groups. Effect estimates for outcomes were estimated using the Mantel-Haenszel method and Cox proportional hazards model and subsequently compared with the corresponding RCT estimates.

RESULTS: Compared to trial populations, real-world study populations were older (range: 63-69 years [RWE] vs. 54-59 years [RCT]), with more females (55-60.5% vs. 39-48.3%) and had a higher prevalence of active cancer (4.2-15.4% vs. 2.5-9.5%). The emulated estimates for effectiveness outcomes showed superior effectiveness of NOAC (AMPLIFY: relative risk 0.81, 95% confidence interval 0.70-0.94; RE-COVER II: hazard ratio [HR] 0.60, 0.37-0.96; Hokusai-VTE: 0.49, 0.31-0.78; EINSTEIN-DVT: 0.54, 0.33-0.89; EINSTEIN-PE: 0.50, 0.34-0.74), when contrasted with trials that showed non-inferiority. For safety outcomes, all emulations except for AMPLIFY and EINSTEIN-DVT yielded results consistent with their corresponding RCTs.

CONCLUSIONS: This study revealed the feasibility of complementing RCTs with RWE studies by using claims data in patients with VTE. Future studies to consider the different demographic characteristics between RCT and RWE populations are needed.

PMID:37775786 | DOI:10.1186/s12916-023-03069-1

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PubMed articles on: Cardio-Oncology

Early Echocardiography and ECG Changes Following Radiotherapy in Patients with Stage II-III HER2-Positive Breast Cancer Treated with Anthracycline-Based Chemotherapy with or without Trastuzumab-Based Therapy

Med Sci Monit. 2023 Sep 20;29:e941754. doi: 10.12659/MSM.941754.