Preventing and Treating Anthracycline Cardiotoxicity: New Insights

Zhou

Front. Cardiovasc. Med.

et al. 2021

Background: Several cardiovascular risk factors have been suggested to be associated with anthracycline-induced cardiotoxicity, but their quantitative effects have not reached a consensus.Methods: We searched PubMed, EMBASE, and Cochrane Library databases for manuscripts published from inception to February 2021, which reported the results of cardiotoxicity due to anthracycline chemotherapy without trastuzumab. Cardiotoxicity defined by any reduction of left ventricular eject fraction (LVEF) to below 50% or a >10% reduction from baseline was defined as the primary endpoint. Odd ratios (OR) with 95% confidence intervals (CI) were calculated using a random-effects model meta-analysis.Results: A total of 7,488 patients receiving anthracycline chemotherapy without trastuzumab were included, who had at least one risk factor at baseline. Hypertension (OR: 1.99; 95% CI: 1.43–2.76), diabetes mellitus (OR: 1.74; 95% CI: 1.11–2.74), and obesity (OR: 1.72; 95% CI: 1.13–2.61) were associated with increased risk of cardiotoxicity. In addition, the relative reduction of global longitudinal strain (GLS) from baseline after anthracycline treatment could significantly improve the detection ability of cardiotoxicity (28.5%, 95% CI: 22.1–35.8% vs. 16.4%, 95% CI: 13.4–19.9%) compared with LVEF. The early detection rate of anthracycline-induced cardiotoxicity (3 months after chemotherapy) by GLS was 30.2% (95% CI: 24.9–36.1%), which is similar with the overall result of GLS.Conclusions: Hypertension, diabetes mellitus, and obesity are associated with increased risk of anthracycline-induced cardiotoxicity, which indicates that corresponding protective strategies should be used during and after anthracycline treatment. The findings of higher detection rate and better early detection ability for cardiotoxicity than LVEF added new proofs for the advantages of GLS in detection of AIC.

Section: Discussionmentioning

confidence: 99%

Risk Factors for Anthracycline-Induced Cardiotoxicity

Zhou

Front. Cardiovasc. Med.

et al. 2021

“…Notably, Dox levels were higher in the heart than in the kidney, spleen, and lungs for both the PDC and Dox treated mice. This is likely due to the cardiotoxicity of Dox as it tends to accumulate in the heart [ 41 , 42 ]. Higher levels of Dox in the heart compared to other organs were also observed by others after mice were treated with free Dox [ 43 , 44 , 45 ].…”

Section: Resultsmentioning

confidence: 99%

“…These results show higher specificity of PDC for the tumor tissue with less systemic toxicities compared to free Dox ( Figure 4 b). The usage of Dox is greatly limited by its cardiotoxic effects, ranging from occult changes in myocardial structure to severe cardiomyopathy and heart failure requiring cardiac transplantation [ 41 ]. Of note, the Dox levels in hearts after PDC treatment were much lower (1.4 times) compared to free Dox treatment group.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of a Keratin 1 Targeting Peptide-Doxorubicin Conjugate in a Mouse Model of Triple-Negative Breast Cancer

et al. 2021

Chemotherapy is the main treatment for triple-negative breast cancer (TNBC), a subtype of breast cancer that is aggressive with a poor prognosis. While chemotherapeutics are potent, these agents lack specificity and are equally toxic to cancer and nonmalignant cells and tissues. Targeted therapies for TNBC treatment could lead to more safe and efficacious drugs. We previously engineered a breast cancer cell targeting peptide 18-4 that specifically binds cell surface receptor keratin 1 (K1) on breast cancer cells. A conjugate of peptide 18-4 and doxorubicin (Dox) containing an acid-sensitive hydrazone linker showed specific toxicity toward TNBC cells. Here, we report the in vivo evaluation of the K1 targeting peptide-Dox conjugate (PDC) in a TNBC cell-derived xenograft mouse model. Mice treated with the conjugate show significantly improved antitumor efficacy and reduced off-target toxicity compared to mice treated with Dox or saline. After six weekly treatments, on day 35, the mice treated with PDC (2.5 mg Dox equivalent/kg) showed significant reduction (1.5 times) in tumor volume compared to mice treated with Dox (2.5 mg/kg). The mice treated with the conjugate showed significantly higher (1.4 times) levels of Dox in tumors and lower (1.3–2.2 times) levels of Dox in other organs compared to mice treated with Dox. Blood collected at 15 min showed 3.6 times higher concentration of the drug (PDC and Dox) in mice injected with PDC compared to the drug (Dox) in mice injected with Dox. The study shows that the K1 targeting PDC is a promising novel modality for treatment of TNBC, with a favorable safety profile, and warrants further investigation of K1 targeting conjugates as TNBC therapeutics.

“…Currently, the exact underlying mechanism of AIC still remains unclear [20], although several hypotheses have been put forward, such as the generation of mitochondrial reactive oxygen species (ROS), disruption of mitochondrial biogenesis, and the induction of ferroptosis [20]. Aside from the cumulative dose, there are some widely known clinical risk factors that play an important role in the development of AIC, i.e., age, gender, hypertension, diabetes and smoking [21].…”

Section: Introductionmentioning

confidence: 99%

POLRMT as a Novel Susceptibility Gene for Cardiotoxicity in Epirubicin Treatment of Breast Cancer Patients

et al. 2021

Anthracyclines are among the most used chemotherapeutic agents in breast cancer (BC). However their use is hampered by anthracycline-induced cardiotoxicity (AIC). The currently known clinical and genetic risk factors do not fully explain the observed inter-individual variability and only have a limited ability to predict which patients are more likely to develop this severe toxicity. To identify novel predictive genes, we conducted a two-stage genome-wide association study in epirubicin-treated BC patients. In the discovery phase, we genotyped over 700,000 single nucleotide variants in a cohort of 227 patients. The most interesting finding was rs62134260, located 4kb upstream of POLRMT (OR = 5.76, P = 2.23 × 10−5). We replicated this association in a validation cohort of 123 patients (P = 0.021). This variant regulates the expression of POLRMT, a gene that encodes a mitochondrial DNA-directed RNA polymerase, responsible for mitochondrial gene expression. Individuals harbouring the risk allele had a decreased expression of POLRMT in heart tissue that may cause an impaired capacity to maintain a healthy mitochondrial population in cardiomyocytes under stressful conditions, as is treatment with epirubicin. This finding suggests a novel molecular mechanism involved in the development of AIC and may improve our ability to predict patients who are at risk.