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4/12/26

ABSTRACT

Combretastatin A4 disodium phosphate (CA4DP) is a prodrug of combretastatin A4 (CA4), a microtubule-disassembling agent that exhibits antitumor effects by inhibiting tumor cell proliferation and inducing morphological changes and apoptosis in vascular endothelial cells in tumors. However, cardiotoxicity induced by ischemia and hypertension is a severe adverse event. In this study, we focused on the fact that phosphodiesterase (PDE) 5 inhibitors dilate the heart and peripheral blood vessels and aimed to investigate whether co-administration of tadalafil, a PDE5 inhibitor, can attenuate cardiotoxicity without altering the antitumor effect of CA4DP. To investigate cardiotoxicity, CA4DP and/or tadalafil were administered to rats, and blood pressure, echocardiography, histopathology, and cGMP concentration in the myocardium were examined. Administration of CA4DP increased systolic blood pressure, decreased cardiac function, lowered cGMP levels in the myocardium, and led to necrosis of myocardial cells. Co-administration of tadalafil attenuated these CA4DP-induced changes. To investigate the antitumor effect, canine mammary carcinoma cell lines (CHMp-13a) and human umbilical vein endothelial cells were cultured with CA4 and/or tadalafil, and cell proliferation and endothelial vascular tube disruption were examined. CHMp-13a cells were transplanted into nude mice and treated with CA4DP and/or tadalafil. CA4-induced inhibition of cell proliferation and disruption of the endothelial vascular tube were not affected by co-treatment with tadalafil, and the antitumor effects of CA4DP in xenograft mice were not reduced by co-administration of tadalafil. These results revealed that myocardial damage induced by CA4DP was attenuated by co-administration of tadalafil while maintaining antitumor efficacy.

PMID:37577366 | PMC:PMC10412959 | DOI:10.1293/tox.2022-0143

07:26

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PubMed articles on: Cardio-Oncology

Lethal ventricular arrhythmia due to entrectinib-induced Brugada syndrome: a case report and literature review

Int Cancer Conf J. 2023 Jun 26;12(4):299-304. doi: 10.1007/s13691-023-00620-y. eCollection 2023 Oct.

ABSTRACT

Entrectinib, a multikinase inhibitor of ROS1and tropomyosin receptor kinases, is recommended to treat ROS1-positive metastatic non-small cell lung cancer (NSCLC). In a previous study, entrectinib-related cardiotoxicity occurred in 2% of patients; however, lethal arrhythmias remain understudied. We encountered a case of fatal arrhythmia due to drug-induced Brugada syndrome caused by entrectinib. An 81-year-old Japanese male with lung adenocarcinoma harboring ROS1-fusion gene was treated with entrectinib. The patient developed lethal arrhythmias three days after drug initiation, including ventricular tachycardia with Brugada-like electrocardiogram changes. Echocardiography and coronary angiography revealed no evidence of acute coronary syndrome or myocarditis. Following the termination of entrectinib, the electrocardiogram abnormality improved within 12 days. Hence, paying special attention to and monitoring electrocardiogram changes is necessary. In addition, it is also necessary to consider early therapeutic interventions and discontinuation of the drug in cases of drug-induced Brugada syndrome.

PMID:37577345 | PMC:PMC10421830 | DOI:10.1007/s13691-023-00620-y

07:26

PubMed articles on: Cardio-Oncology

KMU-191 Induces Apoptosis in Human Clear Cell Renal Cell Carcinoma Caki Cells Through Modulation of Bcl-xL, Mcl-1 (L), c-FLIP (L), and p53 Proteins

J Cancer. 2023 Jul 16;14(12):2224-2235. doi: 10.7150/jca.85650. eCollection 2023.

ABSTRACT

The anti-proliferative effects of a newly developed N3-acyl-N5-aryl-3,5-diaminoindazole analog, KMU-191, have been previously evaluated in various cancer cells. However, the detailed anti-cancer molecular mechanisms of KMU-191 remain unknown. In this study, we investigated anti-cancer mechanisms by which KMU-191 regulates apoptosis-related genes in human clear cell renal cell carcinoma Caki cells. KMU-191 induced poly ADP-ribose polymerase cleavage and caspase-dependent apoptosis. In addition, KMU-191 induced down-regulation of the long form of cellular FADD-like IL-1β-converting enzyme inhibitory protein (c-FLIP (L)) at the transcriptional level as well as that of long form of myeloid cell leukemia (Mcl-1 (L)) and B-cell lymphoma-extra large at the post-transcriptional level. Furthermore, KMU-191-induced apoptosis was closely associated with the Mcl-1 (L) down-regulation, but also partially associated with c-FLIP (L) down-regulation. In contrast, KMU-191 up-regulated p53, which is closely related to KMU-191-induced apoptosis. Although KMU-191 showed cytotoxicity of normal cells, it unusually did not induce cardiotoxicity. Taken together, these results suggest that a multi-target small molecule, N3-acyl-N5-aryl-3,5-diaminoindazole analog, KMU-191 is a potential anti-cancer agent that does not induce cardiotoxicity.

PMID:37576393 | PMC:PMC10414049 | DOI:10.7150/jca.85650

07:26

PubMed articles on: Cardio-Oncology

5-fluorouracil-induced coronary vasospasm: A cardiovascular magnetic resonance imaging case report

Glob Cardiol Sci Pract. 2023 Aug 1;2023(3):e202316. doi: 10.21542/gcsp.2023.16. eCollection 2023 Aug 1.

ABSTRACT

Certain agents frequently used in patients with active neoplasms, such as anthracyclines or HER-2 inhibitors, are commonly recognized for their cardiotoxicity. Fluoropyrimidines have also frequently been associated with cardiotoxic effects. These antimetabolites, including capecitabine, floxuridine, and 5-fluorouracil (5-FU), are commonly used chemotherapeutic agents, particularly for gastrointestinal malignancies. Numerous studies have described variability in the incidence of 5-FU associated cardiotoxicity (0-35%)1. The clinical presentation may vary, from myocardial ischemia, arrhythmias, cardiogenic shock, to sudden cardiac arrest1,2. We describe a case of 5-FU induced coronary vasospasm, confirmed on CMR, in a patient with stage IV colon cancer presenting as myocardial ischemia and new-onset LV systolic dysfunction.

PMID:37575292 | PMC:PMC10422872 | DOI:10.21542/gcsp.2023.16

09:23

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09:23

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PubMed articles on: Cancer & VTE/PE

Simple yet (more?) effective. Venous thromboembolism risk assessment model for germ cell tumour patients receiving first-line chemotherapy

Cancer Med. 2023 Aug 16. doi: 10.1002/cam4.6458. Online ahead of print.

ABSTRACT

BACKGROUND: Germ cell tumours (GCT) are highly curable malignancies. Venous thromboembolism (VTE) is a serious complication, needing better risk assessment models (RAM).

AIM: Identification of VTE incidence and risk factors in metastatic GCT patients starting first-line chemotherapy. Developing a RAM and comparing it to Khorana risk score (KRS) and Padua Prediction Score (PPS).

MATERIAL AND METHODS: We retrospectively analysed GCT patients staged IS-IIIC. VTE risk factors were identified with logistic regression. Area under curve of receiver operating characteristic (AUC-ROC), Akaike and Bayesian Information Criteria (AIC, BIC) were calculated for the developed RAM, KRS and PPS.

RESULTS: Among 495 eligible patients, VTE occurred in 69 (13.9%), including 40 prior to chemotherapy. Vein compression (OR: 8.96; 95% CI: 2.85-28.13; p < 0.001), clinical stage IIIB-IIIC (OR: 5.68; 95% CI: 1.82-17.70; p = 0.003) and haemoglobin concentration (OR for 1 g/dL decrease: 1.32; 95% CI: 1.03-1.67; p = 0.026) were significant in our RAM. KRS ≥ 3 (OR: 3.31; 95% CI: 1.77-6.20; p < 0.001), PPS 4-5 (OR: 3.06; 95% CI: 1.49-6.29; p = 0.002) and PPS > 5 (OR 8.05; 95% CI 3.79-17.13; p < 0.001) correlated with VTE risk. Diagnostic criteria (AUC-ROC, AIC, BIC) for the developed RAM, KRS and PPS were (0.885; 0.567; -1641), (0.588; 0.839; -1576) and (0.700; 0.799; -1585), respectively. In the numerical score, the optimal cut-off point for high-risk was ≥9, with sensitivity, specificity, positive and negative predictive value of 0.78, 0.77, 0.35 and 0.96, respectively.

CONCLUSIONS: Our RAM, based on vein compression, clinical stage and haemoglobin concentration proved superior to both KRS and PPS. VTE is frequent in GCT patients.

PMID:37584231 | DOI:10.1002/cam4.6458

09:23

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PubMed articles on: Cancer & VTE/PE

A case of pulmonary tumor embolism syndrome with thrombus in transit

Respir Med Case Rep. 2023 Jul 20;45:101896. doi: 10.1016/j.rmcr.2023.101896. eCollection 2023.

ABSTRACT

The incidence of pulmonary tumor embolism in patients with solid tumors is estimated to be between 3% and 26% yet is rarely diagnosed. In this case, a 74-year-old male with sarcomatoid variant of urothelial carcinoma and recently diagnosed left renal vein thrombus treated with low-molecular-weight-heparin, presented to the emergency department with acute syncope and dyspnea. He was found to have CT imaging of segmental and subsegmental arterial filling defects, a right atrial filling defect concerning for thrombus in transit and was diagnosed with pulmonary tumor embolism syndrome. The patient was treated with aspiration thrombectomy, with pathology demonstrating sarcomatoid urothelial carcinoma cells. He was initiated on a combination of gemcitabine plus carboplatin to decrease the tumor burden. While pulmonary tumor embolism syndrome is associated with a poor prognosis, prompt diagnosis and initiation of cancer-specific therapies can significantly improve survival.

PMID:37583563 | PMC:PMC10424200 | DOI:10.1016/j.rmcr.2023.101896