Articoli di riviste: "Anthracyclines"

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Sorensen, K., G. Levitt, D. Sebag-Montefiore, C. Bull e I. Sullivan. "Cardiac function in Wilms' tumor survivors." Journal of Clinical Oncology 13, n. 7 (luglio 1995): 1546–56. http://dx.doi.org/10.1200/jco.1995.13.7.1546.

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PURPOSE To study late cardiac function in a single diagnostic group (children with Wilms' tumor) with good long-term survival; to compare patients treated with anthracyclines (doxorubicin) with patients treated without anthracyclines and with a normal child/adolescent group; and to examine the risk factors involved in late cardiac dysfunction. PATIENTS AND METHODS Echocardiographic studies were performed on 97 Wilms' tumor patients treated with anthracyclines (mean cumulative dose, 303 mg/m2) with a mean follow-up time of 7.1 years, on 39 Wilms' tumor patients treated without anthracyclines with a mean follow-up time of 8.9 years, and on 50 normal subjects. Left ventricular (LV) dimensions, end systolic wall stress (a measure of afterload), and load-dependent and -independent measures of contractility were compared between groups. Potential risk factors, including age at diagnosis, follow-up duration, sex, pubertal status, cardiac irradiation, dose-intensity, and cumulative dose of anthracyclines, were studied by multivariate analysis. RESULTS Twenty-five percent of the anthracycline-treated group showed cardiac abnormalities. All but one of these patients had increased LV afterload. Risk factors for increased afterload were anthracycline cumulative dose (P < .05) and anthracycline dose-intensity (P < .02). Wilms' tumor patients treated without anthracyclines had thickened LV walls compared with normal subjects (P < .05). CONCLUSION Total dose and dose-intensity of anthracycline were risk factors for increased LV afterload in long-term Wilms' tumor survivors treated on standard protocols. The increase in afterload accounted for reduced LV shortening, whereas contractility was rarely abnormal. The new finding that Wilms' tumor survivors who do not receive anthracyclines have mild LV hypertrophy may provide some protection against anthracycline-induced cardiotoxic effects.

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Krook, James Edward, Akhil Kumar, Marc L. Fishman, William S. Shimp, Laura Rose Bobolts, Val Fishman, Sharon Davis et al. "Community use of anthracyclines in metastatic breast cancer (MBC)." Journal of Clinical Oncology 31, n. 15_suppl (20 maggio 2013): 1080. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.1080.

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1080 Background: For decades, anthracyclines have been among the most useful treatments for women with MBC. Though recent publications have confirmed an overall decline in the use of anthracyclines in BC, most of that decline was felt to be due to its diminished utilization in the adjuvant management of BC. Current community anthracycline usage pattern in MBC is not known. We investigate and report, herein, how community oncologists in the southeast USA are currently utilizing anthracyclines for MBC. Methods: All chemotherapy treatment requests for HER2+ and HER2- Stage 4 BC were examined, from 2009 through 2012. Chi-Square test was performed for interaction between age and anthracycline utilization, with p-value less than 0.05 considered significant. The proportion of women who had been treated previously in the adjuvant setting with low cumulative doses of anthracyclines, which would have some effect upon subsequent use, was not retrievable. Results: During this span, 420 unique chemotherapy requests were initiated for 247 patients. These included 54 anthracycline requests for 50 MBC patients. The use of anthracyclines for metastatic HER2+ BC was virtually absent (one in 63 requests among 42 patients). The remaining 357 chemotherapy requests were for treatment of 205 HER2- MBC patients. Anthracyclines were employed in 22% of women under 65 years of age and in 25% of those older than 65 (p = 0.77). Approximately 83% (45/54) of anthracycline-requests were for conventional doxorubicin, either alone or in combination with other agents. The rest were for liposomal doxorubicin (6/54) or epirubicin (3/54). Conclusions: Data from the southeast USA identifies that anthracyclines are virtually never used in HER2+ MBC. Even in HER2- MBC, anthracyclines are used in only one out of 4 patients suffering from this disease. The effect of this unheralded alteration in oncology practice must be carefully considered when trends in metastatic breast cancer control are examined. [Table: see text]

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Kumar, Akhil, Marc L. Fishman, William S. Shimp, Laura Rose Bobolts, James Edward Krook, Val Fishman, Sharon Davis et al. "Community use of anthracyclines for adjuvant HER2-positive breast cancer (BC)." Journal of Clinical Oncology 31, n. 15_suppl (20 maggio 2013): e11609-e11609. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e11609.

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e11609 Background: Anthracyclines remain among the most active agents for the treatment of BC. NSABP B-31, NCCTG N9831 and HERA, each employing anthracyclines followed by trastuzumab in adjuvant HER2+ BC, demonstrated significant reduction in the risk of recurrence and improvement in survival. A fourth study, BCIRG-006, compared a non-anthracycline containing regimen, TCH, to an anthracycline based regimen, AC-TH. Both arms had similar overall survival, but there was a higher incidence of cardiac events in patients who received anthracycline. HER2-analyses in randomized adjuvant trials, in the pre-trastuzumab era, comparing anthracycline with non-anthracycline chemotherapy regimens, show that HER2+ BC derives greater benefit from anthracycline use. TOP2A coamplification, which occurs in 35% of HER2-positive patients, has shown a direct association with anthracycline benefit in several studies. We investigate and report, herein, the ways in which community oncologists are currently treating these patients. Methods: All treatment requests for adjuvant trastuzumab were examined, from 2009 through 2012. Chi-square analysis at 0.05α was used to test for interaction of age group to type of treatment. Results: During this span, oncologists requested adjuvant trastuzumab for 121 patients. In 10% (12/121) of patients, adjuvant trastuzumab alone, without chemotherapy and with or without hormonal therapy, was requested. Among patients who also received adjuvant chemotherapy (109), 35% (38/109), received anthracyclines. There was no relationship of anthracycline-usage with BC stage (data not shown) or patient age (Chi Sq p = 0.73). Adjuvant trastuzumab, without chemotherapy, was requested more often for the elderly (20% versus 4%; Chi Sq p = 0.003). Conclusions: Anthracyclines are utilized in adjuvant HER2+ BC in only about a third of patients, regardless of BC stage or patient age. The availability of a reliable, inexpensive, and convenient test to predict which patients are most likely to benefit from anthracyclines, over other options, would be useful. [Table: see text]

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Neppelenbroek, Suzanne I. M., Yvonne M. Geurts, Berthe M. P. Aleman, Cecile P. M. Janus, Saskia E. Rademakers, Roel J. de Weijer, Richard W. M. Van Der Maazen et al. "Anthracycline exposure and breast cancer risk in female Hodgkin lymphoma survivors." Journal of Clinical Oncology 39, n. 15_suppl (20 maggio 2021): 12074. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.12074.

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12074 Background: Female Hodgkin lymphoma (HL) survivors treated with chest radiotherapy (RT) at a young age have a strongly increased risk of breast cancer (BC). Recently concern has been raised that anthracyclines may also increase BC risk, based on studies in childhood cancer survivors with/without a history of chest RT. So far, the association between anthracyclines and BC risk has not been examined in cancer survivors treated at adolescent/adult ages. Now that RT dose and volumes are decreasing, the potential contribution of anthracyclines to BC risk is an important issue. Methods: We assessed BC risk in a cohort of 2314 female 5-year HL survivors, treated at ages 15-50 years and diagnosed between 1965 and 2008 in 20 Dutch hospitals. Treatment factors were time-dependently included in the analysis, focusing on the effect of anthracycline exposure on BC risk. Results: After a median follow-up of 18.8 years, 258 women developed invasive BC or ductal carcinoma in situ as a subsequent malignancy. The 30-year cumulative incidence was 15.0% (95% Confidence Interval (CI) 12.8-17.4%). Mantle field RT (or other RT involving both axillae) was associated with increased risk of BC (Hazard ratio (HR) 1.9; 95% CI 1.2-2.8) compared to no supradiaphragmatic RT or RT to the neck only (Table 1). Gonadotoxic treatment (>4.2 g/m2 procarbazine or pelvic RT) significantly decreased this risk. In a multivariable analysis, anthracycline exposure was associated with increased BC risk (HR 1.8; 95% CI 1.3-2.5) in patients who received a cumulative dose of >200 mg/m2. Among patients exposed to gonadotoxic treatment, the HR of BC associated with >200mg/m2 anthracyclines was 3.8 (95% CI 2.0-7.2), with a trend for higher risk with higher anthracycline dose (HR 1.58 per 100mg/m2 anthracycline, p<0.001). Conclusions: Our results suggest an association of anthracyclines with BC risk in HL survivors. Also when accounting for the protective effect of gonadotoxic treatment on RT-associated BC risk, anthracyclines significantly contributed to a higher BC risk.[Table: see text]

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Blanco, Javier G., Can-Lan Sun, Wendy Landier, Lu Chen, Diego Esparza-Duran, Wendy Leisenring, Allison Mays et al. "Anthracycline-Related Cardiomyopathy After Childhood Cancer: Role of Polymorphisms in Carbonyl Reductase Genes—A Report From the Children's Oncology Group". Journal of Clinical Oncology 30, n. 13 (1 maggio 2012): 1415–21. http://dx.doi.org/10.1200/jco.2011.34.8987.

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Purpose Carbonyl reductases (CBRs) catalyze reduction of anthracyclines to cardiotoxic alcohol metabolites. Polymorphisms in CBR1 and CBR3 influence synthesis of these metabolites. We examined whether single nucleotide polymorphisms in CBR1 (CBR1 1096G>A) and/or CBR3 (CBR3 V244M) modified the dose-dependent risk of anthracycline-related cardiomyopathy in childhood cancer survivors. Patients and Methods One hundred seventy survivors with cardiomyopathy (patient cases) were compared with 317 survivors with no cardiomyopathy (controls; matched on cancer diagnosis, year of diagnosis, length of follow-up, and race/ethnicity) using conditional logistic regression techniques. Results A dose-dependent association was observed between cumulative anthracycline exposure and cardiomyopathy risk (0 mg/m2: reference; 1 to 100 mg/m2: odds ratio [OR], 1.65; 101 to 150 mg/m2: OR, 3.85; 151 to 200 mg/m2: OR, 3.69; 201 to 250 mg/m2: OR, 7.23; 251 to 300 mg/m2: OR, 23.47; > 300 mg/m2: OR, 27.59; Ptrend < .001). Among individuals carrying the variant A allele (CBR1:GA/AA and/or CBR3:GA/AA), exposure to low- to moderate-dose anthracyclines (1 to 250 mg/m2) did not increase the risk of cardiomyopathy. Among individuals with CBR3 V244M homozygous G genotypes (CBR3:GG), exposure to low- to moderate-dose anthracyclines increased cardiomyopathy risk when compared with individuals with CBR3:GA/AA genotypes unexposed to anthracyclines (OR, 5.48; P = .003), as well as exposed to low- to moderate-dose anthracyclines (OR, 3.30; P = .006). High-dose anthracyclines (> 250 mg/m2) were associated with increased cardiomyopathy risk, irrespective of CBR genotype status. Conclusion This study demonstrates increased anthracycline-related cardiomyopathy risk at doses as low as 101 to 150 mg/m2. Homozygosis for G allele in CBR3 contributes to increased cardiomyopathy risk associated with low- to moderate-dose anthracyclines, such that there seems to be no safe dose for patients homozygous for the CBR3 V244M G allele. These results suggest a need for targeted intervention for those at increased risk of cardiomyopathy.

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Rybczyńska-Tkaczyk, Kamila. "Enhanced Efficiency of the Removal of Cytostatic Anthracycline Drugs Using Immobilized Mycelium of Bjerkandera adusta CCBAS 930". Molecules 26, n. 22 (12 novembre 2021): 6842. http://dx.doi.org/10.3390/molecules26226842.

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The aim of this study was to evaluate the bioremoval of anthracycline antibiotics (daunomycin-DNR, doxorubicin–DOX, and mitoxantrone-MTX) by immobilized mycelium of B. adusta CCBAS 930. The activity of oxidoreductases: versatile peroxidases (VP), superoxide dismutase (SOD), catalase (CAT), and glucose oxidase (GOX), and the levels of phenolic compounds (PhC) and free radicals (SOR) were determined during the biotransformation of anthracyclines by B. adusta strain CCBAS 930. Moreover, the phytotoxicity (Lepidium sativum L.), biotoxicity (MARA assay), and genotoxicity of anthracyclines were evaluated after biological treatment. After 120 h, more than 90% of anthracyclines were removed by the immobilized mycelium of B. adusta CCBAS 930. The effective biotransformation of anthracyclines was correlated with detoxification and reduced genotoxicity.

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Torkkell, Sirke, Tero Kunnari, Kaisa Palmu, Juha Hakala, Pekka Mäntsälä e Kristiina Ylihonko. "Identification of a Cyclase Gene Dictating the C-9 Stereochemistry of Anthracyclines from Streptomyces nogalater". Antimicrobial Agents and Chemotherapy 44, n. 2 (1 febbraio 2000): 396–99. http://dx.doi.org/10.1128/aac.44.2.396-399.2000.

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ABSTRACT Nogalamycin is an anthracycline antibiotic produced byStreptomyces nogalater. Its aglycone has a unique stereochemistry (7S, 9S, 10R) compared to that of most other anthracyclines (7S, 9R, 10R). The gene snoaL, encoding a nogalonic acid methyl ester cyclase for nogalamycin, was used to generate nogalamycinone, demonstrating that the single cyclase dictates the C-9 stereochemistry of anthracyclines.

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Krell, J., C. Harper-Wynne, D. Miles, V. Misra, S. Cleator, D. Krell e C. Palmieri. "What is the evidence for rechallenging with anthracyclines or taxanes in metastatic breast cancer? A review of the data". Journal of Clinical Oncology 27, n. 15_suppl (20 maggio 2009): 1072. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.1072.

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1072 Background: Anthracyclines and taxanes are widely used in the adjuvant setting for high risk, early stage breast cancer. This raises the issue of what is the optimal therapy for those patients who relapse, and what the potential role, if any, there is for rechallenge with these agents. The current evidence base for rechallenging with anthracyclines/anthracediones and taxanes in metastatic breast cancer (MBC) is examined in this study. Methods: Medline/Pubmed database searches were performed upto October 2008 to identify studies in which patients (pts) were rechallenged with anthracyclines/anthracediones or taxanes in MBC. Results: The efficacy data, as well as the safety data relating to neurotoxicity and cardiotoxicity from these studies, are summarized in the Table. Twenty-seven studies were identified (20=anthracycline/anthracedione, 7= taxane) of which only two were prospective studies. Both were small (n= 74 & 51) and related to anthracycline rechallenging. Conclusions: Evidence exists to support rechallenging with anthracyclines and taxanes. However, there are few prospective data on reexposure to taxanes and no data comparing anthracyclines versus taxanes following adjuvant exposure to both agents, supporting the need for clinical trials in this area. Such trials should ideally incorporate a cross-over design at treatment failure, which would shed light on the optimal sequence in which these agents should be administered. [Table: see text] No significant financial relationships to disclose.

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Chen, Wei-Wu, Twan Ying Chang, Shu-Min Huang, Ching-Hung Lin, Chiun Hsu, Ann-Lii Cheng e Yen-Shen Lu. "The first two lines of chemotherapy for anthracycline-naïve metastatic breast cancer: A comparative study of efficacy between anthracyclines and nonanthracyclines." Journal of Clinical Oncology 30, n. 15_suppl (20 maggio 2012): 1061. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.1061.

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1061 Background: For anthracycline-naïve metastatic breast cancer (AN-MBC) patients, past evidence indicated that anthracyclines are beneficial in the first-two lines of palliative chemotherapy but with considerable toxicities. However, with the provision of newer chemotherapies, comparative studies addressing the efficacy between anthracyclines and non-anthracyclines in the first-two lines of palliative chemotherapy for AN-MBC were lacking. Methods: We collectedclinicopathological characteristics of AN-MBC patients who had received palliative chemotherapy in National Taiwan University Hospital between 2001 and 2006. Patients were classified as anthracycline or non-anthracycline group according to the first-two lines of chemotherapy. Kaplan-Meier method and log-rank test were used for the estimation and comparison of both overall survival (OS) and time to treatment failure of the first-two lines (TTF2).Cox proportional hazard model was used for OS and TTF2. Best composite response rate (BCRR) were compared with logistic regression test. Results: A total of 109 (43.1%) patients in the anthracycline group and 144 (56.9%) patients in non-anthracycline group were analyzed. Between these two groups, the distributions of clinicopathological variables were generally similar and their median OS (33.3 vs 34.2 months, p = 0.179), TTF2 (13.3 vs 12.7 months, p = 0.104), and BCRR (59.5 vs 61.1%, p = 0.81) were not significantly different. Subgroup analysis showed that patients in the anthracycline group had a trend toward better OS in the estrogen receptor (ER) negative/ human epidermal growth factor receptor type II (HER2) positive subtype (median OS 58.0 vs 31.2 months, p = 0.081). In multivariate analysis, patients in the anthracycline group had a trend toward better OS (HR 0.72, 95% CI 0.52 - 1.00, p = 0.052). However, the exclusion of ER-/Her2+ subtype attenuated the impact of early anthracycline treatment on OS (HR 0.82, 95% CI 0.56 - 1.18, p = 0.28). Conclusions: Our study demonstrated that anthracyclines may not be mandatory in the first-two lines of palliative chemotherapy for AN-MBC but may be more beneficial to ER-/Her2+ subtype patients.

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Gianni, Luca, Larry Norton, Norman Wolmark, Thomas M. Suter, Gianni Bonadonna e Gabriel N. Hortobagyi. "Role of Anthracyclines in the Treatment of Early Breast Cancer". Journal of Clinical Oncology 27, n. 28 (1 ottobre 2009): 4798–808. http://dx.doi.org/10.1200/jco.2008.21.4791.

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Purpose To review data relating to anthracyclines in the adjuvant treatment of early breast cancer. Design This is a report from a seminar in which the future of anthracyclines in the adjuvant treatment of breast cancer was considered. In particular, the question of whether anthracyclines should now be discarded and replaced by taxanes was addressed. Results Accumulating data from large randomized trials indicate that genetic markers may have a role in predicting sensitivity to cytotoxic drugs. However, no reliable, validated test is available for predicting sensitivity to anthracyclines in particular. Topoisomerase IIα amplification and/or deletion, especially in conjunction with human epidermal growth factor receptor-2 amplification, has been proposed to fulfill this role but more data are needed. Currently, only one published trial has shown that a taxane-based regimen may be superior to an anthracycline-based regimen, but several trials indicate that combinations including both anthracyclines and taxanes may be better still. Further studies aimed at optimizing anthracyclines and taxanes in combination, and integrating biologic agents, seem to be the way forward. There is no validated test that can determine whether anthracyclines can be of greater benefit than other agents for individual patients. Conclusion Anthracyclines have been extensively tested in clinical trials spanning several decades; currently, there are insufficient data to recommend replacing them in the adjuvant treatment of breast cancer.

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Suarato, Antonino, Francesco Angelucci e Cristina Geroni. "Ring-B Modified Anthracyclines". Current Pharmaceutical Design 5, n. 3 (marzo 1999): 217–27. http://dx.doi.org/10.2174/1381612805666230109215627.

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One of the most investigated classes of antitumor drugs is represented by anthracyclines. Over thirty years since the original discovery of daunorubicin and doxorubicin thousands of anthracycline analogues have been synthesized and tested to identify compounds superior to the parent drugs in terms of increased therapeutic effectiveness, reduced toxicity or both. Previous structure-activity studies had shown that minor modifications of the anthracycline structure can result not only in active agents, but, more importantly, analogues with reduced cardiotoxicity and activity on multi drug resistance. The fact that 4- demethoxydaunorubicin showed higher potency than c.launorubicin and a reduced cardiotoxicity, prompted us to explore novel analogues with altered substitution patterns on the anthraquinone system, particularly ring-B. In this review we will describe total synthesis and antitumor activity of three classes of derivatives: whereby one hydroxyl group in ring-B was either removed or replaced with nitro or amino groups. While these modifications yielded anthracyclines with a promising pharmacological activity, they did not modify activity on multidrug resistant (MDR) tumors. On the other hand, introduction of morpholino group in the sugar part of these new molecules, dramatically increased activity on MDR tumors. We conclude that activity on MDR tumors is not bound to modifications in the aglycone moiety of anthracyclines.

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Dozic, Sanela, Erin J. Howden, James R. Bell, Kimberley M. Mellor, Lea M. D. Delbridge e Kate L. Weeks. "Cellular Mechanisms Mediating Exercise-Induced Protection against Cardiotoxic Anthracycline Cancer Therapy". Cells 12, n. 9 (4 maggio 2023): 1312. http://dx.doi.org/10.3390/cells12091312.

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Anthracyclines such as doxorubicin are widely used chemotherapy drugs. A common side effect of anthracycline therapy is cardiotoxicity, which can compromise heart function and lead to dilated cardiomyopathy and heart failure. Dexrazoxane and heart failure medications (i.e., beta blockers and drugs targeting the renin–angiotensin system) are prescribed for the primary prevention of cancer therapy-related cardiotoxicity and for the management of cardiac dysfunction and symptoms if they arise during chemotherapy. However, there is a clear need for new therapies to combat the cardiotoxic effects of cancer drugs. Exercise is a cardioprotective stimulus that has recently been shown to improve heart function and prevent functional disability in breast cancer patients undergoing anthracycline chemotherapy. Evidence from preclinical studies supports the use of exercise training to prevent or attenuate the damaging effects of anthracyclines on the cardiovascular system. In this review, we summarise findings from experimental models which provide insight into cellular mechanisms by which exercise may protect the heart from anthracycline-mediated damage, and identify knowledge gaps that require further investigation. Improved understanding of the mechanisms by which exercise protects the heart from anthracyclines may lead to the development of novel therapies to treat cancer therapy-related cardiotoxicity.

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Gennari, A., M. Sormani, M. Costantini, P. Pronzato, R. Rosso e P. Bruzzi. "Anthracycline regimens versus CMF in the adjuvant treatment of early breast cancer (EBC): A matter of difference". Journal of Clinical Oncology 24, n. 18_suppl (20 giugno 2006): 569. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.569.

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569 Background: Anthracycline-based adjuvant chemotherapy (CT) in EBC was found, in the latest EBCTCG overview, to be associated with a 15% reduction in mortality, when compared to CMF. However, differences among trials, and specifically the use of suboptimal experimental arms (underdosed anthracyclines) and non conventional CMF (i.v.), require a careful interpretation of this finding. Methods: To evaluate the reduction in mortality, associated to different anthracycline and CMF regimens, we performed a systematic overview of abstracted data from published randomised trials comparing CMF with anthracyclines. Those studies including other drugs were excluded. Fifteen retrieved trials, comprising 15.831 women, were divided into 6 groups according to the type of CMF (oral or i.v.), and to the type of anthracycline regimen: 3 drugs (FAC/FEC), 2/1 drugs (AC/EC, A/E) and sequential schedules (Anthra→CMF). From each study, the estimates of the Hazard Ratio (HR; anthra vs CMF) and of its variance were abstracted or estimated from the presented results. HRs from studies of the same group were combined according to standard meta-analytic techniques. Summary estimates of HR for oral or i.v. CMF and for different anthracycline schedules were similarly obtained. Results: The overall comparison confirms a superiority of anthracyclines over CMF (HR 0.83 - 95%CI 0.77–0.90, p<0.001). HRs in the 6 groups of studies are reported in the table . When i.v. CMF is compared to any anthracycline regimen, the HR is 0.76 (95%CI 0.67–0.86, p<0.001; heterogeneity p 0.01), while with oral CMF, the HR is 0.88 (95%CI 0.80–0.97, p 0.01; heterogeneity p 0.06). Conclusions: The magnitude of the survival benefit of anthracyclines over CMF seems to be strongly affected by the type of anthracycline regimen and by the type of CMF, the largest effect being observed in trials using sequential schedules and i.v. CMF. Final results will be presented at the meeting, including evaluation of regimen type and its effects on toxicity and quality of life. [Table: see text] No significant financial relationships to disclose.

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Egas Bejar, Daniela E., Joy M. Fulbright, Fernando F. Corrales-Medina, Mary E. Irwin, Blake Johnson e Joya Chandra. "Uncovering Cardioprotective Strategies For Anthracycline Therapy By Analysis Of Redox and Apoptotic Effects". Blood 122, n. 21 (15 novembre 2013): 1293. http://dx.doi.org/10.1182/blood.v122.21.1293.1293.

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Abstract Anthracyclines are among the most powerful drugs used for the treatment of leukemia, however their use has been associated with cardiotoxicity. Reactive oxygen species (ROS) are generated in both cancer and normal cells after anthracycline exposure and have been implicated in both early and late onset cardiotoxicity. Counteracting this ROS generation are intracellular antioxidants such as the ubiquitous antioxidant glutathione (GSH), levels of which are depleted upon anthracycline exposure. Basal expression of GSH pathway components and other antioxidants vary greatly between different cell types. Due to this differential expression of cellular antioxidants in cardiomyocytes versus leukemia cells, we posit that anthracyclines exert distinct effects on oxidative stress and consequent apoptosis induction in leukemia cells and nontransformed hematopoietic cells (PBMC) relative to cardiomyocytes. As a result, we expect potentially varied mechanisms of cell death induction in these cell lines after anthracycline treatment. To test this hypothesis, the acute leukemia cell lines Jurkat and ML-1 and the cardiomyocyte line H9C2 were used. Dose responses with the anthracyclines, doxorubicin and daunorubicin, were carried out and trypan blue exclusion and propidium iodide staining followed by flow cytometry were used to assess viability and DNA fragmentation respectively. Cardiomyocytes had a 25-150 fold higher IC50 value than the acute leukemia cell lines, indicating selectivity. To assess whether apoptosis was induced by anthracyclines, caspase 3 activity was measured and found to be increased at 24 hours in Jurkat cells which preceded decreases in viability, supporting an apoptotic mechanism of cell death. GSH levels also decreased markedly after 24 hours of treatment with anthracyclines in this cell line, however, a pan-caspase inhibitor did not block GSH depletion, indicating that these events occur independent of each other. To evaluate whether antioxidants conferred protection against loss of viability in all cell types, cells were pretreated for at least 30 minutes with antioxidants and then treated with doxorubicin and daunorubicin for 24 hours. Antioxidants used were N-acetylcysteine (NAC, a GSH precursor and amino acid source), GSH ethyl ester (cell permeable form of GSH), tiron (free radical scavenger) and trolox (a water soluble form of vitamin E). GSH ethylester did not prevent cytotoxicity of anthracyclines in acute leukemia lines or cardiomyocytes. Therefore boosting GSH levels in leukemia cells does not reverse cytotoxicity. Trolox, however, did block anthracycline induced cell death in ML-1 cells, suggesting that vitamin E supplementation would counteract leukemia cell specific effects of anthracyclines on AML cells. Tiron protected PBMC from doxorubicin cytotoxicity but did not protect leukemia cells or cardiomyocytes, hinting at a protective strategy for normal non-leukemia blood cells. Interestingly, NAC did not interfere with the cytotoxic effects of anthracyclines on acute leukemia cells or PBMC, but protected H9C2 cells from daunorubicin cytotoxicity. Taken together, these data reveal differential protective effects of antioxidants in cardiomyocytes and PBMCs relative to ALL and AML cells. Our work indicates that NAC can protect cardiomyocytes without interfering with anthracycline cytotoxicity in acute leukemia cells. In humans, one randomized control trial tested the addition of NAC to doxorubicin therapy, detecting no evidence of cardioprotective activity by chronic administration of NAC. However, the schedule used for administration of NAC in that study may not have been optimal, and biomarkers for oxidative stress reduction by NAC were not incorporated into the trial. Previously, other antioxidants have been used with very limited clinical success and possible contributing factors include inadequate sample size, choice of agent, dose used, duration of intervention and the lack of biomarker endpoints. Designing a cardioprotective and antioxidant strategy with attention to these factors may prove to be efficacious in protecting cardiac cells without interfering with the antitumoral effect of anthracyclines. To this end, our data suggests that trolox and vitamin E analogues should not be used in acute leukemia as they may interfere with the cytotoxic action of anthracyclines but NAC or cysteine may be used as cardioprotectants. Disclosures: No relevant conflicts of interest to declare.

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Behrouzian, Mahsa, Babak Najibi, Sabahat Haghi, Chehreh Mahdavi, Kaveh Jaseb e Ehsan Ghaedi. "Prevalence of Major Cardiac Events of Anthracycline-Induced Cardiotoxicity in Southwestern Iran: Different Response Patterns to Cumulative Dose". Current Drug Therapy 15, n. 1 (14 gennaio 2020): 78–84. http://dx.doi.org/10.2174/1574885514666190311145607.

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Background: Anthracyclines are widely used chemotherapeutic agents in several cancers. Since its use, survival improved significantly among cancer patients and has been reported to be up to 80%. However, anthracyclines possess several cardiac, renal and hematological toxicities which limit their use in practice. Cardiotoxicity is still the most important and dose-limiting side effect of anthracycline treatment. Here we aimed to investigate the frequency of anthracyclineinduced cardiomyopathy in pediatric malignancies in Khuzestan Province, Iran. Methods: A total of 112 patients were enrolled in the present study. Patients were allocated to the case or control group based on receiving anthracycline. Echocardiographic examinations were performed by a cardiologist. Electrocardiograms were also recorded. Results: We showed that cancer patients who underwent anthracycline treatment showed cardiomyopathy as defined by lower LVEF (Left Ventricular Ejection Fraction) among patients (p = 0.041). Abnormal LVEF was reported with a frequency of about 9.5% in patients (p = 0.026). However, LVFS (Left Ventricular Fraction Shortening), QRS voltage and QT interval did not differ significantly between treatment and control groups. Our data analysis revealed that this difference is mainly related to high cumulative dose since high cumulative dose of anthracycline (>300 mg/m2) leads to lower LVEF and LVFS and higher QRS voltage in comparison with lower cumulative dose (<300 mg/m2) and control group; but there was no significant difference between low dose and control group. Different age groups and type of malignancy including hematological and solid tumors did not show any significant differences for echocardiographic and electrocardiograms parameters. Conclusion: In our study, lower LVEF among patients who received anthracyclines were mainly related to a high cumulative dose of anthracyclines, which emphasizes the effect of cumulative dose for cardiotoxic effects. Larger studies are needed to investigate possible other risk factors for cardiotoxicity.

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Khan, Meraj A., Adam D’Ovidio, Harvard Tran e Nades Palaniyar. "Anthracyclines Suppress Both NADPH Oxidase- Dependent and -Independent NETosis in Human Neutrophils". Cancers 11, n. 9 (7 settembre 2019): 1328. http://dx.doi.org/10.3390/cancers11091328.

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Neutrophil extracellular traps (NETs) are cytotoxic DNA-protein complexes that play positive and negative roles in combating infection, inflammation, organ damage, autoimmunity, sepsis and cancer. However, NETosis regulatory effects of most of the clinically used drugs are not clearly established. Several recent studies highlight the relevance of NETs in promoting both cancer cell death and metastasis. Here, we screened the NETosis regulatory ability of 126 compounds belonging to 39 classes of drugs commonly used for treating cancer, blood cell disorders and other diseases. Our studies show that anthracyclines (e.g., epirubicin, daunorubicin, doxorubicin, and idarubicin) consistently suppress both NADPH oxidase-dependent and -independent types of NETosis in human neutrophils, ex vivo. The intercalating property of anthracycline may be enough to alter the transcription initiation and lead NETosis inhibition. Notably, the inhibitory doses of anthracyclines neither suppress the production of reactive oxygen species that are necessary for antimicrobial functions nor induce apoptotic cell death in neutrophils. Therefore, anthracyclines are a major class of drug that suppresses NETosis. The dexrazoxane, a cardioprotective agent, used for limiting the side effects of anthracyclines, neither affect NETosis nor alter the ability of anthracyclines to suppress NETosis. Hence, at correct doses, anthracyclines together with dexrazoxane could be considered as a therapeutic candidate drug for suppressing unwanted NETosis in NET-related diseases.

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de Vries, Elisabeth G. E., e Jan G. Zijlstra. "Morpholinyl anthracyclines: Option for reversal of anthracycline resistance". European Journal of Cancer and Clinical Oncology 26, n. 6 (gennaio 1990): 659–60. http://dx.doi.org/10.1016/0277-5379(90)90110-f.

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Marinello, Jessica, Maria Delcuratolo e Giovanni Capranico. "Anthracyclines as Topoisomerase II Poisons: From Early Studies to New Perspectives". International Journal of Molecular Sciences 19, n. 11 (6 novembre 2018): 3480. http://dx.doi.org/10.3390/ijms19113480.

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Mammalian DNA topoisomerases II are targets of anticancer anthracyclines that act by stabilizing enzyme-DNA complexes wherein DNA strands are cut and covalently linked to the protein. This molecular mechanism is the molecular basis of anthracycline anticancer activity as well as the toxic effects such as cardiomyopathy and induction of secondary cancers. Even though anthracyclines have been used in the clinic for more than 50 years for solid and blood cancers, the search of breakthrough analogs has substantially failed. The recent developments of personalized medicine, availability of individual genomic information, and immune therapy are expected to change significantly human cancer therapy. Here, we discuss the knowledge of anthracyclines as Topoisomerase II poisons, their molecular and cellular effects and toxicity along with current efforts to improve the therapeutic index. Then, we discuss the contribution of the immune system in the anticancer activity of anthracyclines, and the need to increase our knowledge of molecular mechanisms connecting the drug targets to the immune stimulatory pathways in cancer cells. We propose that the complete definition of the molecular interaction of anthracyclines with the immune system may open up more effective and safer ways to treat patients with these drugs.

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Montaigne, David, Christopher Hurt e Remi Neviere. "Mitochondria Death/Survival Signaling Pathways in Cardiotoxicity Induced by Anthracyclines and Anticancer-Targeted Therapies". Biochemistry Research International 2012 (2012): 1–12. http://dx.doi.org/10.1155/2012/951539.

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Anthracyclines remain the cornerstone of treatment in many malignancies but these agents have a cumulative dose relationship with cardiotoxicity. Development of cardiomyopathy and congestive heart failure induced by anthracyclines are typically dose-dependent, irreversible, and cumulative. Although past studies of cardiotoxicity have focused on anthracyclines, more recently interest has turned to anticancer drugs that target many proteins kinases, such as tyrosine kinases. An attractive model to explain the mechanism of this cardiotoxicity could be myocyte loss through cell death pathways. Inhibition of mitochondrial transition permeability is a valuable tool to prevent doxorubicin-induced cardiotoxicity. In response to anthracycline treatment, activation of several protein kinases, neuregulin/ErbB2 signaling, and transcriptional factors modify mitochondrial functions that determine cell death or survival through the modulation of mitochondrial membrane permeability. Cellular response to anthracyclines is also modulated by a myriad of transcriptional factors that influence cell fate. Several novel targeted chemotherapeutic agents have been associated with a small but worrying risk of left ventricular dysfunction. Agents such as trastuzumab and tyrosine kinase inhibitors can lead to cardiotoxicity that is fundamentally different from that caused by anthracyclines, whereas biological effects converge to the mitochondria as a critical target.

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Qiao, Xiaohang, Sabina Y. van der Zanden, Dennis P. A. Wander, Daniel M. Borràs, Ji-Ying Song, Xiaoyang Li, Suzanne van Duikeren et al. "Uncoupling DNA damage from chromatin damage to detoxify doxorubicin". Proceedings of the National Academy of Sciences 117, n. 26 (17 giugno 2020): 15182–92. http://dx.doi.org/10.1073/pnas.1922072117.

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The anthracycline doxorubicin (Doxo) and its analogs daunorubicin (Daun), epirubicin (Epi), and idarubicin (Ida) have been cornerstones of anticancer therapy for nearly five decades. However, their clinical application is limited by severe side effects, especially dose-dependent irreversible cardiotoxicity. Other detrimental side effects of anthracyclines include therapy-related malignancies and infertility. It is unclear whether these side effects are coupled to the chemotherapeutic efficacy. Doxo, Daun, Epi, and Ida execute two cellular activities: DNA damage, causing double-strand breaks (DSBs) following poisoning of topoisomerase II (Topo II), and chromatin damage, mediated through histone eviction at selected sites in the genome. Here we report that anthracycline-induced cardiotoxicity requires the combination of both cellular activities. Topo II poisons with either one of the activities fail to induce cardiotoxicity in mice and human cardiac microtissues, as observed for aclarubicin (Acla) and etoposide (Etop). Further, we show that Doxo can be detoxified by chemically separating these two activities. Anthracycline variants that induce chromatin damage without causing DSBs maintain similar anticancer potency in cell lines, mice, and human acute myeloid leukemia patients, implying that chromatin damage constitutes a major cytotoxic mechanism of anthracyclines. With these anthracyclines abstained from cardiotoxicity and therapy-related tumors, we thus uncoupled the side effects from anticancer efficacy. These results suggest that anthracycline variants acting primarily via chromatin damage may allow prolonged treatment of cancer patients and will improve the quality of life of cancer survivors.

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Herzig, R. H., H. M. Lazarus, S. N. Wolff, G. L. Phillips e G. P. Herzig. "High-dose cytosine arabinoside therapy with and without anthracycline antibiotics for remission reinduction of acute nonlymphoblastic leukemia." Journal of Clinical Oncology 3, n. 7 (luglio 1985): 992–97. http://dx.doi.org/10.1200/jco.1985.3.7.992.

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Seventy-eight patients with acute nonlymphoblastic leukemia in relapse were treated with high-dose cytosine arabinoside (3 g/m2 intravenously (IV) every 12 hours for 12 doses) alone, or with three days of anthracycline antibiotics (doxorubicin 20 mg/m2 or daunorubicin 30 mg/m2 IV daily) after completing the course of cytosine arabinoside. Consolidation and maintenance therapy was not given. When anthracyclines were added there was no increase in frequency or severity of nonhematologic toxicity including conjunctivitis, photophobia, dermatitis, cerebellar dysfunction, and gastrointestinal disturbance. All 78 patients achieved aplasia of the bone marrow. Five patients in each group died before bone marrow recovery. The use of anthracyclines did not prolong bone marrow recovery, with both groups demonstrating adequate granulocyte and platelet counts about four weeks after beginning treatment. Forty-one (53%) of the total 78 patients achieved a complete remission. In patients not clinically resistant to conventional-dose cytosine arabinoside, both regimens were equally effective inducing a complete remission (high-dose cytosine arabinoside alone, 12/19 [63%]; with anthracycline, 11/17 [65%], P = .270); in patients clinically resistant, the regimen including anthracycline was superior (15/27 [56%] v 3/15 [20%], P = .022). The duration of unmaintained response was similar (median, five months), but the longest remissions occurred when anthracyclines were used. Thus, high-dose cytosine arabinoside is effective in producing remissions in relapsed patients with acute nonlymphoblastic leukemia, and the addition of an anthracycline enhances this effect.

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Levina, V. D., M. G. Poltavskaya, V. P. Sedov, P. Sh Chomakhidze, L. V. Bolotina, T. I. Deshkina, M. D. Kuklina et al. "The role of left ventricle global longitudinal srain in prediction of chemotherapy — induced cardiotoxicity in breast cancer patients treated by low and moderate cumulative doses of anthracyclines". Medical alphabet, n. 33 (12 gennaio 2023): 19–26. http://dx.doi.org/10.33667/2078-5631-2022-33-19-26.

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Objective. To evaluate the alterations of Global longitudinsl strain (GLS) and it’s value for prediction of cardiotoxicity of low to moderate cumulative doses of anthracyclines. Methods. Forty-nine women 50 ± 10 years old with breast cancer, treated with anthracyclines (cumulative dose of 251 ± 60 mg/m2) were enrolled in the study. Echocardiography with GLS measurement was performed at baseline, at the end of anthracycline treatment, then every 3 months during 1 year. Cardiotoxicity was defined as a decline in left ventricular ejection fraction (LVEF) of at least 10 % to ≤ 53 %. Results. There was a significant increase in mean LVESV and LVEDV and decrease of GLS (р < 0,05) but not LVEF at 3 month post anthracycline treatment. Cardiotoxicity was detected in 8 patients (16 %) with moderate baseline risk. Absolute ≥ 4 % reduction of GLS during follow-up, GLS andpercent of it’s reduction from baseline to 3 month post-anthracycline were predictive of cardiotoxicity (AUC = 0,822 and 0,870, respectively). The reduction in GLS of >12,5 % from baseline at 3 month post anthracyclines was predictive of cardiotoxicity with sensitivity of 80 % and specificity of 95 %. Conclusions. GLS and its reduction from baseline has shown predictive value for development of cardiotoxicity in patients with moderate risk treated with low-to moderate cumulative doses of antracyclines. Additional echocardiography with GLS assessment at 3–6 month after completion of anthracycline treatment may be recommended irrespective of cardiotoxicity risk.

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Al-Batran, S., M. Scholz e E. Jäger. "Anthracycline-rechallenge using pegylated liposomal doxorubicin (PLD) in previously treated patients with metastatic breast cancer (MBC): A meta-analysis using pooled individual data from four prospective trials". Journal of Clinical Oncology 27, n. 15_suppl (20 maggio 2009): 1047. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.1047.

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1047 Background: Few data are available on the efficacy of anthracycline rechallenge using PLD. Methods: Pooled individual data from 4 prospective trials (Keller, J Clin Oncol. 2004; O'Brien, Ann Oncol. 2004; Al-Batran, Br J Cancer. 2006; and Al-Batran, Oncology. 2006) were utilized to evaluate the activity of PLD in pts with MBC previously treated with conventional anthracyclines. Primary endpoint was clinical benefit rate (CBR), defined as objective response or stable disease, both lasting ≥ 6 months. CBR was assessed in the entire group (primary hypothesis CBR ≥ 30%) and in pre-defined subgroups of pts depending on the most important features of their prior anthracycline-based therapy. Results: The studies comprised a total 935 pts, of whom 274 pts had received PLD after prior exposure to conventional anthracyclines. At the time of PLD therapy, these (274) pts were heavily pre-treated for MBC (median lines of previous chemotherapy 4, range 1 to 9, and 93.4% of pts received PLD after ≥ 2 previous chemotherapies for MBC). Prior anthracycline treatment was adjuvant, anti-metastatic, or both in 14%, 46%, or 40% of pts, respectively. The overall CBR from PLD was 32.2% (95% CI, 26.7%-37.8%), with no difference between pts who were considered anthracycline resistant (based on the study records) and those who were not (31.9% vs. 31.6%, respectively; p = 1). There was also no difference in CBR from PLD between pts who received prior anthracyclines adjuvant only (33.3%), anti-metastatic only (34.4%) or both (29.4%; p = 0.71). There was a trend towards a higher CBR in pts who received PLD at > 12 months vs ≤ 12 months since the end of their prior conventional anthracycline treatment (34.2% vs. 26.3%, respectively; p = 0.21). Higher CBR (up to 47%) and longer survival times were observed in pts without taxane pretreatment or with a low number of previous chemotherapies, most likely reflecting a less advanced disease in these pts. Conclusions: This meta-analysis demonstrates a clinical benefit from PLD in MBC pts previously treated with multiple chemotherapies, including anthracyclines. Interestingly, the CBR was independent of resistance to, setting of, or time since previous conventional anthracycline therapy. [Table: see text]

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Menna, Pierantonio, e Emanuela Salvatorelli. "Primary Prevention Strategies for Anthracycline Cardiotoxicity: A Brief Overview". Chemotherapy 62, n. 3 (2017): 159–68. http://dx.doi.org/10.1159/000455823.

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The clinical use of doxorubicin and other antitumor anthracyclines is limited by a dose-related risk of cardiomyopathy and heart failure which may occur “on treatment” or any time, from months to years, after completing chemotherapy. Dose reductions diminish the incidence of cardiac events attributable to anthracyclines, but heart failure still occurs in some patients exposed to low or moderate anthracycline doses. Because anthracyclines improve the life expectancy of patients with, for example, breast cancer or lymphomas, preventing or diminishing the risk of early or delayed cardiotoxicity is of obvious clinical importance. Here, we briefly review some potential strategies of primary prevention that are based on what we know about the molecular mechanisms of cardiotoxicity, and what can be done, or might be done, to interfere with the pharmacokinetic, pharmacodynamic, and genetic determinants of cardiotoxicity.

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Veiga, Lene H. S., Rochelle E. Curtis, Lindsay M. Morton, Diana Withrow, Rebecca M. Howell, Susan A. Smith, Rita Weathers et al. "Combined effect of radiotherapy and anthracyclines on risk of breast cancer among female childhood cancer survivors: A report from the Childhood Cancer Survivor Study (CCSS)." Journal of Clinical Oncology 37, n. 15_suppl (20 maggio 2019): 10053. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.10053.

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10053 Background: Breast cancer is a common late-effect for female childhood cancer survivors and chest radiotherapy is an established risk factor. Recent findings showed that treatment with anthracyclines also increases breast cancer risk. However, the risk from the combined effect of radiotherapy and anthracyclines is unknown. Methods: We conducted a matched case-control study of 271 subsequent breast cancer and 1044 controls nested within the CCSS - a North-American cohort of five-year survivors of childhood cancer, diagnosed from 1970-1986 and followed-up through 2016. Detailed treatment records were abstracted to estimate radiation dose (Gy) to the breast cancer location and ovaries and calculate cumulative chemotherapy doses (mg/m2). Multivariable conditional logistic regression was used to estimate Odds ratios (OR) and 95% confidence intervals (CI). Results: Breast cancer risk increased linearly with radiation dose to the breast (OR per 10Gy = 3.9, 95%CI:2.5-6.5) and decreased with increasing ovarian dose (p < 0.01). Adjusted for radiation dose, the highest quartile of dose (455+mg/m2) of anthracyclines was associated with a 3.8-fold increased risk of breast cancer (95%CI:1.8-8.2) compared to no anthracyclines. This risk increased with cumulative anthracycline dose (p-trend < 0.01) and was non-significantly higher for ER+ than ER- breast cancers. For a breast dose of 10+Gy, the OR was 19.1 (95%CI:7.6-48.0) with anthracyclines versus 9.6 (95%CI:4.4-20.7) without anthracyclines, compared to 0- < 1Gy breast dose and no anthracyclines (p-additive interaction = 0.04). Conclusions: The combination of anthracyclines and radiotherapy doses to the breast can markedly increase breast cancer risk compared to those who receive neither treatment. Our results can be used to inform risk management for childhood cancer patients treated in the past, as well as project potential breast cancer risk from current treatment protocols.

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Aplenc, R., J. Blanco, W. Leisenring, S. Davies, M. Relling, L. Robison, C. Sklar, M. Stovall e S. Bhatia. "Polymorphisms in candidate genes in patients with congestive heart failure (CHF) after childhood cancer: A Report from the Childhood Cancer Survivor Study (CCSS)". Journal of Clinical Oncology 24, n. 18_suppl (20 giugno 2006): 9004. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.9004.

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9004 Background: In cancer survivors, CHF associated with the use of anthracyclines is an important clinical complication. Risk factors for anthracycline associated cardiac toxicity, including cumulative dose, gender, and age, have been described. However, these risk factors do not fully explain the observed clinical variability. Notably, the potential role of genetic risk factors has not been studied. A recent “unifying hypothesis” postulates that the early cardiac damage is mediated mostly by oxidative stress while the more chronic type of toxicity is induced by anthracycline alcohol metabolites synthesized by carbonyl reductases (CBRs). Therefore we hypothesized that genetic polymorphisms in genes encoding for enzymes involved in oxidative stress pathways, and the metabolism of anthracyclines may impact on the risk of anthracycline-related cardiotoxicity. Methods: We conducted a nested case-control study within a cohort of 5,739 patients enrolled in the CCSS. Forty-seven cases with CHF and 195 matched controls (matched for demographics, follow-up and treatment) were genotyped for 10 genetic polymorphisms in 7 genes: catalase (CAT), GSTP, GSTT, GSTM, superoxide dismutase (SOD 1), NQO1, and CBR3. Results: In the subjects who received anthracyclines, multivariable analyses of CHF risk, adjusted for gender, smoking history, recurrence, and family history of heart disease, showed the GSTP +313A>G polymorphism was a significant risk factor, HR = 5.0, p = 0.01 for the A/G genotype vs. A/A; HR = 3.3, p = 0.19 for the G/G genotype vs. A/A. In addition, a suggested association between CBR3 V244M polymorphism and the risk of CHF after treatment with anthracyclines, HR=10.2, p=0.06 for G/G vs. A/A; HR = 4.0, p=0.18 for G/A vs. A/A was seen in an identical multivariable analysis. Conclusions: These data suggest that specific polymorphic genetic variants on a panel of candidate genes relevant to the anthracycline pharmacodynamics may modify the risk of CHF in childhood cancer survivors. Future studies to further refine the role of these novel genetic risk factors affecting a large population are warranted. No significant financial relationships to disclose.

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Armenian, Saro, e Smita Bhatia. "Predicting and Preventing Anthracycline-Related Cardiotoxicity". American Society of Clinical Oncology Educational Book, n. 38 (maggio 2018): 3–12. http://dx.doi.org/10.1200/edbk_100015.

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Anthracyclines (doxorubicin, daunorubicin, epirubicin, and idarubicin) are among the most potent chemotherapeutic agents and have truly revolutionized the management of childhood cancer. They form the backbone of chemotherapy regimens used to treat childhood acute lymphoblastic leukemia, acute myeloid leukemia, Hodgkin lymphoma, Ewing sarcoma, osteosarcoma, and neuroblastoma. More than 50% of children with cancer are treated with anthracyclines. The clinical utility of anthracyclines is compromised by dose-dependent cardiotoxicity, manifesting initially as asymptomatic cardiac dysfunction and evolving irreversibly to congestive heart failure. Childhood cancer survivors are at a five- to 15-fold increased risk for congestive heart failure compared with the general population. Once diagnosed with congestive heart failure, the 5-year survival rate is less than 50%. Prediction models have been developed for childhood cancer survivors (i.e., after exposure to anthracyclines) to identify those at increased risk for cardiotoxicity. Studies are currently under way to test risk-reducing strategies. There remains a critical need to identify patients with childhood cancer at diagnosis (i.e., prior to anthracycline exposure) such that noncardiotoxic therapies can be contemplated.

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Mata, Danilo Giffoni M. M., Matthew Castelo, Rinku Sutradhar, Lena Nguyen, Neil Faught, Danielle Rodin, Ezra Hahn et al. "Abstract P4-06-10: Is Anthracycline Chemotherapy Essential in the Treatment of Women with Breast Cancer? – A Real World Comparison in the Neoadjuvant Setting". Cancer Research 83, n. 5_Supplement (1 marzo 2023): P4–06–10—P4–06–10. http://dx.doi.org/10.1158/1538-7445.sabcs22-p4-06-10.

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Abstract Background: Breast cancer is the second most commonly diagnosed cancer in North American women. The administration of neoadjuvant chemotherapy (NAC) is the mainstay of treatment for individuals with high risk disease in an effort to reduce the extent of surgery, evaluate the role of additional adjuvant therapies (based on pathologic response to NAC), and improve disease-free and overall survival (OS). Anthracyclines have been shown to increase response rates leading to a greater likelihood of pathologic complete response compared to non-anthracycline regimens. However, for some individuals anthracyclines are omitted from the NAC regimen due to toxicities including greater immunosuppression, cardiac toxicity and risk of acute leukemia. We established a population-based cohort of individuals treated with NAC for breast cancer. We report the outcomes of women selected for treatment with non-anthracycline NAC compared to those treated with anthracyclines. Methods: This is a retrospective population-based cohort study using linked health administrative data held at the Institute for Clinical Evaluative Sciences (ICES) in Ontario, Canada. We identified adult women diagnosed with stage I-III breast cancer (ICD-10 C50^) between 2012 and 2020 who received NAC. Administration of at least 50% of the planned chemotherapy regimen was required. We excluded patients with bilateral breast cancer, previous malignancy and male sex. NAC regimens were classified as anthracycline and non-anthracycline-containing regimens. To address confounding between those receiving anthracycline and other regimens, we built a propensity score model including patient and disease characteristics. The association with OS was calculated using Cox proportional hazards models, and breast cancer-specific survival (BCSS) was calculated using cause-specific Cox proportional hazards models. Models were adjusted for the propensity score, radiation treatment as a time-varying covariate, age, socioeconomic status, breast cancer stage and receptor sub-type, as well as Charlson comorbidity index. Results: A total of 4,180 women were identified with a median follow up of 62 months (IQR 44 – 85). Of these, 279 (6.7%) were treated with non-anthracycline regimens compared to 3,901 treated with anthracycline. Patients who received non-anthracyclines were older (median 62 years vs. 50 years; p < 0.001), and less likely to have stage III disease (33.0% vs. 48.7%; p < 0.001), and harbor triple-negative breast cancer (TNBC) (14.0% vs. 24.4%; p < 0.001). They were more likely to have no recorded comorbidities (89.2% vs. 96.5%; p < 0.001), undergo mastectomy (82.1% vs. 71.9%; p < 0.001), and sentinel lymph node biopsy (44.4% vs. 32.3%; p < 0.001). After propensity score and multivariable adjustment, women selected for treatment with non-anthracycline regimens had similar OS (HR 0.85, 95% CI 0.60-1.21) and BCSS (cause-specific HR 0.76, 95% CI 0.46-1.25) compared to those treated with anthracyclines. When stratified by stage, women treated with non-anthracycline regimens did not have significantly higher incidences of breast cancer death or death from any cause (stages I, II, and III Gray’s Test p-value all > 0.1). The mean OS was 7.2 years for women who received non-anthracycline regimens (95% CI 7.0 – 7.4) compared to 7.9 years for those who received anthracycline (95% CI 7.9 – 8.0) (log-rank p = 0.100). Conclusions: Women with stage I-III breast cancer treated with non-anthracycline NAC regimens are a highly selected population. These patients were older and healthier, with earlier stage disease and more favorable subtype (i.e. non-TNBC) when compared to those treated with anthracycline NAC. Our results demonstrate that women were well selected to omit anthracyclines and did not have worse survival outcomes. Further research is needed to better understand in whom anthracycline can be safely omitted. Citation Format: Danilo Giffoni M. M. Mata, Matthew Castelo, Rinku Sutradhar, Lena Nguyen, Neil Faught, Danielle Rodin, Ezra Hahn, Omolara Fatiregun, Cindy Fong, Sabina Trebinjac, Andrea Eisen, Lawrence Paszat, Katarzyna Jerzak, Eileen Rakovitch. Is Anthracycline Chemotherapy Essential in the Treatment of Women with Breast Cancer? – A Real World Comparison in the Neoadjuvant Setting [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-06-10.

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Hamilton, Joseph Z., Kerry Klussman, Rebecca Mahzereh, Jessica Simmons, Michelle Ulrich, Shyra J. Gardai, Peter D. Senter e Patrick J. Burke. "Abstract 2013: Oxidized anthracycline payloads induce anti-tumor immunogenic cell-death and show linker-dependent tolerability when delivered as ADCs". Cancer Research 83, n. 7_Supplement (4 aprile 2023): 2013. http://dx.doi.org/10.1158/1538-7445.am2023-2013.

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Abstract Novel payloads with orthogonal mechanisms of action (MOAs) to established ADC technologies are important for expanding the utility of antibody-drug conjugates (ADCs) in cancer treatment. Anthracyclines, a class of cytotoxic small molecules that include important clinical chemotherapeutics such as doxorubicin, have long been of interest to the ADC field due to their high potency and unique MOA. Interest in anthracyclines has increased in recent years due to their status as canonical inducers of immunogenic-cell death (ICD), a feature that may lead to more durable tumor regressions and increased synergy with immune checkpoint blockade. In this work, we investigate several drug-linkers based on oxidized derivatives of the highly potent anthracycline analogue PNU-159682. Resultant ADCs are potent and immunologically specific with linker-dependent bystander activity in co-culture cytotoxicity assays displaying heterogeneous antigen (Ag+/Ag-) expression. Rodent in vivo anti-tumor activity and tolerability are shown with significant differences emerging between the toxicity profile of the cleavable and non-cleavable analogues. In vitro, tumor cells treated with anthracycline ADCs showed key hallmarks of ICD including markers of endoplasmic reticulum (ER) stress and the induction of ICD damage-associated molecular patterns (DAMPs) such as HMGB1 and ATP. In vivo mouse xenograft studies show increased tumoral F4/80+ macrophage infiltration by IHC in anthracycline ADC treated animals relative to controls. ADCs delivering monomethyl auristatin E (MMAE) show comparable activity in ICD assays, confirming MMAE as an ICD inducing ADC payload alongside canonical inducers such as anthracyclines. Our results indicate there is a therapeutic window in rodents alongside ICD induction by anthracycline ADCs, positioning anthracyclines as a potentially impactful class of ADC payloads. Citation Format: Joseph Z. Hamilton, Kerry Klussman, Rebecca Mahzereh, Jessica Simmons, Michelle Ulrich, Shyra J. Gardai, Peter D. Senter, Patrick J. Burke. Oxidized anthracycline payloads induce anti-tumor immunogenic cell-death and show linker-dependent tolerability when delivered as ADCs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2013.

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Kremer, L. C. M., E. C. van Dalen, M. Offringa, J. Ottenkamp e P. A. Voûte. "Anthracycline-Induced Clinical Heart Failure in a Cohort of 607 Children: Long-Term Follow-Up Study". Journal of Clinical Oncology 19, n. 1 (1 gennaio 2001): 191–96. http://dx.doi.org/10.1200/jco.2001.19.1.191.

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PURPOSE: To determine the early and late cumulative incidence of anthracycline-induced clinical heart failure (A-CHF) after anthracycline therapy in childhood and to identify associated risk factors. PATIENTS AND METHODS: The cumulative incidence of A-CHF and the risk factors of A-CHF were assessed in a cohort of 607 children who had been treated with anthracyclines between 1976 and 1996. For 96% of the cohort, we obtained the clinical status up to at least January 1997. The mean follow-up time was 6.3 years. RESULTS: The cumulative incidence of A-CHF was 2.8%, after a mean follow-up time of 6.3 years and a mean cumulative dose of anthracyclines of 301 mg/m2. A cumulative dose of anthracycline higher than 300 mg/m2 was associated with an increased risk of A-CHF (relative risk, 11.8; 95% confidence interval, 1.6 to 59.5) compared with a cumulative dose lower than 300 mg/m2. The estimated risk of A-CHF increased with time after the start of anthracycline chemotherapy to 2% after 2 years and 5% after 15 years. CONCLUSION: Up to 5% of patients will develop A-CHF 15 years after treatment, and patients treated with a cumulative dose of anthracyclines higher than 300 mg/m2 are at highest risk for A-CHF. This is thus a considerable and serious problem among these young patients. The findings reinforce the need for strategies for early detection of patients at risk for A-CHF and for the evaluation of other chemotherapeutic possibilities or cardioprotective agents in relation to the survival.

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Fulbright, Joy Marie, e Joya Chandra. "“Limiting Anthracycline-Induced Cardiotoxicity Using Amrubicin in Leukemia Systems”." Blood 114, n. 22 (20 novembre 2009): 3760. http://dx.doi.org/10.1182/blood.v114.22.3760.3760.

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Abstract Abstract 3760 Poster Board III-696 The overall survival of pediatric cancer patients has greatly improved over the last forty years in part due to the introduction of anthracyclines into therapeutic regimens. However, a significant limitation of anthracyline use is cardiotoxicity by this class of drugs. The mechanism most often cited as contributing to anthracycline cardiotoxicity is the production of reactive oxygen species (ROS) and subsequent damage to mitochondria, resulting in activation of the apoptotic cascade. Because heart tissue contains more mitochondria than other organ sites, this mechanism is particularly damaging to this organ site. Newer, less toxic anthracyclines are being developed and amrubicin, a completely synthetic anthracycline with potent topoisomerase II inhibition, is one such compound and is approved in Japan for the treatment of small cell and non-small cell lung cancer. In animal studies amrubicin has demonstrated decreased cardiotoxicity compared to doxorubicin, and in Phase I/II clinical trials in lymphomas and solid tumors has demonstrated single agent activity and an improved early cardiotoxicity profile. Our goal was to elucidate the role of ROS in the decreased cardiotoxicity observed with amrubicin exposure and to test the ability of amrubicin to promote cell death in leukemia cells. We used a rat cardiomyocyte cell line model (H9c2 cells) to quantify oxidative stress after exposure to amrubicin or other anthracyclines. Flow cytometry was used to evaluate superoxide levels after the cells were treated for 24 hours and stained with hydroethidium (HE). Interestingly, at equimolar doses (500 nM, 1 μM, 2 μM and 3 μM), cardiomyocytes treated with amrubicin produced less superoxide than cells treated with an equivalent dose of daunorubicin. These results suggest that ROS-mediated damage to cardiomyocytes is less after amrubicin exposure as compared to daunorubicin. The anti-leukemia efficacy of amrubicin was also evaluated as compared to other anthracyclines. Apoptosis induction in three different acute lymphocytic and myelocytic leukemia cell lines; Jurkat, ML-1 and KG-1 was measured using propidium iodide staining followed by flow cytometric analysis to yield cell cycle distributions. The percentage of the population with subdiploid amounts of DNA were representative of cells undergoing apoptotic DNA fragmentation. Using this method, we found that all three anthracyclines caused cell death after 24 hours of exposure. In order to assess the role of oxidative stress in anthracycline mediated cell death in leukemia cells, we measured ROS levels using equipotent doses of the drugs that elicited a 50% increase in the subdiploid population at 24 hours. In Jurkat and ML-1 cells both daunorubicin and doxorubicin significantly increased superoxide levels compared to control. Amrubicin also increased superoxide levels in Jurkat cells compared to cells treated with diluent alone. To establish a relationship between the observed oxidative stress and DNA fragmentation, we treated Jurkat cells with daunorubicin and doxorubicin with and without pretreatment with NAC (N-acetyl-cysteine), an antioxidant. NAC pretreatment significantly decreased superoxide levels, but did not abrogate the anthracyclines' promotion of apoptotic DNA fragmentation. These results suggest that ROS may not be essential for anthracycline cytotoxicity in leukemia cells. Since ROS are promoting cardiotoxic effects, yet appear dispensible for anti-leukemia effects, anthracyclines that cause less ROS, such as amrubicin, may prove to be better treatment options in pediatric cancer patients for whom anthracycline exposure is indicated. Furthermore, our data raises the possibility that amrubicin's decreased cardiotoxicity could be enhanced by administering antioxidants to patients without compromising the drug's anti-tumor effects. Disclosures: Chandra: Pharmion Corporation: Research Funding.

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Harahsheh, Ashraf, Sanjeev Aggarwal, Michael D. Pettersen e Thomas L’Ecuyer. "Diastolic function in anthracycline-treated children". Cardiology in the Young 25, n. 6 (23 settembre 2014): 1130–35. http://dx.doi.org/10.1017/s1047951114001760.

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AbstractBackground: Anthracyclines are effective medications for childhood cancer. Their limitation is the risk of cardiomyopathy. Although diastolic dysfunction has been described in patients who received anthracyclines, cardiac monitoring has focused on systolic function, which is abnormal in up to 41% of the patients. We conducted a study to assess diastolic function utilising transmitral inflow Doppler velocities and tissue Doppler imaging in anthracycline-treated children 5 years post-therapy. Methods: This was a retrospective study on 63 anthracycline-treated patients. Echocardiographic parameters included peak early and late transmitral inflow Doppler velocities (E, A), E/A ratio, E deceleration time, and tissue Doppler imaging early and late diastolic mitral annulus velocities (E′, A′), E/E′ ratio, and E′/A′ ratio. Results: All indices of diastolic function that we measured were normal in the anthracycline-treated patients. Conclusion: We conclude that diastolic function assessed by transmitral inflow Doppler velocities and tissue Doppler imaging is normal in anthracycline-treated children 5 years after completion of treatment. Further longitudinal study is needed to determine whether diastolic function becomes abnormal with time in this patient population.

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Piccart-Gebhart, Martine J., Tomasz Burzykowski, Marc Buyse, George Sledge, James Carmichael, Hans-Joachim Lück, John R. Mackey et al. "Taxanes Alone or in Combination With Anthracyclines As First-Line Therapy of Patients With Metastatic Breast Cancer". Journal of Clinical Oncology 26, n. 12 (20 aprile 2008): 1980–86. http://dx.doi.org/10.1200/jco.2007.10.8399.

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Purpose Taxanes (paclitaxel or docetaxel) have been sequenced or combined with anthracyclines (doxorubicin or epirubicin) for the first-line treatment of advanced breast cancer. This meta-analysis uses data from all relevant trials to detect any advantages of taxanes in terms of tumor response, progression-free survival (PFS), and survival. Patients and Methods Individual patient data were collected on eight randomized combination trials comparing anthracyclines + taxanes (+ cyclophosphamide in one trial) with anthracyclines + cyclophosphamide (+ fluorouracil in four trials), and on three single-agent trials comparing taxanes with anthracyclines. Combination trials included 3,034 patients; single-agent trials included 919 patients. Results Median follow-up of living patients was 43 months, median survival was 19.3 months, and median PFS was 7.1 months. In single-agent trials, response rates were similar in the taxanes (38%) and in the anthracyclines (33%) arms (P = .08). The hazard ratios for taxanes compared with anthracyclines were 1.19 (95% CI, 1.04 to 1.36; P = .011) for PFS and 1.01 (95% CI, 0.88 to 1.16; P = .90) for survival. In combination trials, response rates were 57% (10% complete) in taxane-based combinations and 46% (6% complete) in control arms (P < .001). The hazard ratios for taxane-based combinations compared with control arms were 0.92 (95% CI, 0.85 to 0.99; P = .031) for PFS and 0.95 (95% CI, 0.88 to 1.03; P = .24) for survival. Conclusion Taxanes were significantly worse than single-agent anthracyclines in terms of PFS, but not in terms of response rates or survival. Taxane-based combinations were significantly better than anthracycline-based combinations in terms of response rates and PFS, but not in terms of survival.

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Megias-Vericat, Juan Eduardo, David Martínez-Cuadrón, Joaquin Martínez López, Juan Miguel Bergua, Mar Tormo, Josefina Serrano, Ataulfo González et al. "DIFFERENCES IN EX-VIVO CHEMOSENSITIVITY TO ANTHRACYCLINES IN FIRST LINE ACUTE MYELOID LEUKEMIA". Mediterranean Journal of Hematology and Infectious Diseases 11, n. 1 (26 febbraio 2019): e2019016. http://dx.doi.org/10.4084/mjhid.2019.016.

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BACKGROUND: Induction schedules in acute myeloid leukemia (AML) are based on combinations of cytarabine and anthracyclines. The choice of the anthracycline employed has been widely studied in multiple clinical trials showing similar complete remission rates. MATERIALS AND METHODS: Using an ex vivo test we have analyzed if a subset of AML patients may respond differently to cytarabine combined with idarubicin, daunorubicin or mitoxantrone. Bone marrow (BM) samples of 198 AML patients were incubated for 48 hours in 96 well plates, each well containing different drugs or drug combinations at different concentrations. Ex vivo drug sensitivity analysis was made using the PharmaFlow platform maintaining the BM microenvironment. Drug response was evaluated as depletion of AML blast cells in each well after incubation. Annexin V-FITC was used to quantify the ability of the drugs to induce apoptosis, and pharmacological responses were calculated using pharmacokinetic population models. RESULTS: Similar dose-respond graphs were generated for the three anthracyclines, with a slight decrease in EC50 with idarubicin (p=1.462E-06), whereas the interpatient variability of either drug was large. To identify those cases of selective sensitivity to anthracyclines, potency was compared, in terms of area under the curve. Differences in anthracycline monotherapy potency greater than 30% from 3 pairwise comparisons were identified in 28.3% of samples. Furthermore, different sensitivity was detected in 8.2% of patients comparing combinations of cytarabine and anthracyclines. DISCUSSION: A third of the patients could benefit of the use of this test in the first line induction therapy selection, although it should be confirmed in a clinical trial specifically designed.

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Creutzig, Ursula, Sylke Diekamp, Martin Zimmermann e Dirk Reinhardt. "Long Term Data on Anthracycline Cardiotoxicity in 547 Children with AML." Blood 108, n. 11 (1 novembre 2006): 2014. http://dx.doi.org/10.1182/blood.v108.11.2014.2014.

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Abstract Anthracyclines are effective antineoplastic drugs in acute mylogenous leukemia (AML) and dose intensity and cumulative doses are especially important. However, the use of anthracyclines is limited by cardiotoxicity, which occurs already at 300 mg/m2 cumulative doses (given as daunorubicin dosage) in children. To evaluate anthracycline-associated cardiomyopathy in pediatric AML-patients, the incidence of late clinical and subclinical cardiotoxicity (using echocardiography) was analysed in studies AML-BFM 93 and 98. Out of a total of 1,207 patients under 18 years, 547 (45%) patients were eligible for the analysis of late cardiotoxicity - de novo AML: 470 of 1,010 (46%), AML-Down syndrome: 69 of 121 (57%), secondary AML 8 of 76 (11%) -, median follow-up 5.3 years (0.8–11.7 years) after diagnosis. The cumulative dose of anthracyclines was risk-adapted between 300 and 450 mg/m2 or even higher in patients with secondary AML. Results: Late cardiomyopathy was seen in 16 patients, cumulative incidence (CI) after 11 years 5±1% (de novo patients: 4±1%), including 4 of 38 patients (10.5%) who suffered already from early cardiomyopathy. Nine of these 16 patients (CI 2.5±1%) showed clinical symptoms, with persistent abnormal shortening fraction in 5 of them, which led to death in one AML-Down syndrome patient. Late subclinical cardiomyopathy occurred temporarily in 7 patients. Late clinical cardiomyopathy mainly effected patients with a second anthracycline therapy (3 of 8 with AML as secondary malignancy) and those with early cardiotoxicity. Using anthracyclines risk-adapted or administering long-term infusion might have contributed to the low rate of cardiomyopathy in AML de novo patients.

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Cheong, Alison, Sean McGrath e Suzanne Cutts. "Anthracyclines". WikiJournal of Medicine 5, n. 1 (6 dicembre 2018): 1. http://dx.doi.org/10.15347/wjm/2018.001.

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&NA;. "Anthracyclines". Reactions Weekly &NA;, n. 433 (gennaio 1993): 6. http://dx.doi.org/10.2165/00128415-199304330-00012.

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&NA;. "Anthracyclines". Reactions Weekly &NA;, n. 371 (ottobre 1991): 4–5. http://dx.doi.org/10.2165/00128415-199103710-00011.

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&NA;. "Anthracyclines". Reactions Weekly &NA;, n. 1293 (marzo 2010): 9–10. http://dx.doi.org/10.2165/00128415-201012930-00021.

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Desmedt, Christine, Angelo Di Leo, Evandro de Azambuja, Denis Larsimont, Benjamin Haibe-Kains, Jean Selleslags, Suzette Delaloge et al. "Multifactorial Approach to Predicting Resistance to Anthracyclines". Journal of Clinical Oncology 29, n. 12 (20 aprile 2011): 1578–86. http://dx.doi.org/10.1200/jco.2010.31.2231.

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Purpose Validated biomarkers predictive of response/resistance to anthracyclines in breast cancer are currently lacking. The neoadjuvant Trial of Principle (TOP) study, in which patients with estrogen receptor (ER) –negative tumors were treated with anthracycline (epirubicin) monotherapy, was specifically designed to evaluate the predictive value of topoisomerase II-α (TOP2A) and develop a gene expression signature to identify those patients who do not benefit from anthracyclines. Patients and Methods The TOP trial included 149 patients, 139 of whom were evaluable for response prediction analyses. The primary end point was pathologic complete response (pCR). TOP2A and gene expression profiles were evaluated using pre-epirubicin biopsies. Gene expression data from ER-negative samples of the EORTC (European Organisation for Research and Treatment of Cancer) 10994/BIG (Breast International Group) 00-01 and MDACC (MD Anderson Cancer Center) 2003-0321 neoadjuvant trials were used for validation purposes. Results A pCR was obtained in 14% of the evaluable patients in the TOP trial. TOP2A amplification, but not protein overexpression, was significantly associated with pCR (P ≤ .001 v P ≤ .33). We developed an anthracycline-based score (A-Score) combining three signatures: a TOP2A gene signature and two previously published signatures related to tumor invasion and immune response. The A-Score was characterized by a high negative predictive value ([NPV]; NPV, 0.98; 95% CI, 0.90 to 1.00) overall and in the human epidermal growth factor receptor 2 (HER2) –negative and HER2-positive subpopulations. Its performance was independently confirmed in the anthracycline-based arms of the two validation trials (BIG 00-01: NPV, 0.83; 95% CI, 0.64 to 0.94 and MDACC 2003-0321: NPV, 1.00; 95% CI, 0.80 to 1.00). Conclusion Given its high NPV, the A-Score could become, if further validated, a useful clinical tool to identify those patients who do not benefit from anthracyclines and could therefore be spared the non-negligible adverse effects.

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Cheah, Irwin K., Richard M. Y. Tang, Xiaoyuan Wang, Karishma Sachaphibulkij, Suet Yen Chong, Lina H. K. Lim, Jiong-Wei Wang e Barry Halliwell. "Protection against Doxorubicin-Induced Cardiotoxicity by Ergothioneine". Antioxidants 12, n. 2 (30 gennaio 2023): 320. http://dx.doi.org/10.3390/antiox12020320.

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Background: Anthracyclines such as doxorubicin remain a primary treatment for hematological malignancies and breast cancers. However, cardiotoxicity induced by anthracyclines, possibly leading to heart failure, severely limits their application. The pathological mechanisms of anthracycline-induced cardiac injury are believed to involve iron-overload-mediated formation of reactive oxygen species (ROS), mitochondrial dysfunction, and inflammation. The dietary thione, ergothioneine (ET), is avidly absorbed and accumulated in tissues, including the heart. Amongst other cytoprotective properties, ET was shown to scavenge ROS, decrease proinflammatory mediators, and chelate metal cations, including Fe2+, preventing them from partaking in redox activities, and may protect against mitochondrial damage and dysfunction. Plasma ET levels are also strongly correlated to a decreased risk of cardiovascular events in humans, suggesting a cardioprotective role. This evidence highlights ET’s potential to counteract anthracycline cardiotoxicity. Methods and Findings: We investigated whether ET supplementation can protect against cardiac dysfunction in mice models of doxorubicin-induced cardiotoxicity and revealed that it had significant protective effects. Moreover, ET administration in a mouse breast cancer model did not exacerbate the growth of the tumor or interfere with the chemotherapeutic efficacy of doxorubicin. Conclusion: These results suggest that ET could be a viable co-therapy to alleviate the cardiotoxic effects of anthracyclines in the treatment of cancers.

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Attina’, Giorgio, Silvia Triarico, Alberto Romano, Palma Maurizi, Stefano Mastrangelo e Antonio Ruggiero. "Serum Biomarkers for the Detection of Cardiac Dysfunction in Childhood Cancers Receiving Anthracycline-Based Treatment". Biomedical and Pharmacology Journal 15, n. 3 (29 settembre 2022): 1311–21. http://dx.doi.org/10.13005/bpj/2468.

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Anthracyclines are routinely used in cancer chemotherapy in many childhood cancers. A serious adverse effect of doxorubicin chemotherapy is cardiotoxicity which may lead to congestive heart failure for long-term survivors years after treatment. Currently, echocardiography is used to control the heart function during anthracyclines therapy. B-type natriuretic peptide (BNP) and NT-proBNP as well as cardiac troponins have been proposed as clinical markers for subclinical anthracycline-induced cardiotoxicity. The BNP and pro-BNP can be easily measured in plasma and initial data indicate that the NT-proBNP could be sensitive predictor for the development of congestive heart failure.

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Paukovcekova, Silvia, Maria Krchniakova, Petr Chlapek, Jakub Neradil, Jan Skoda e Renata Veselska. "Thiosemicarbazones Can Act Synergistically with Anthracyclines to Downregulate CHEK1 Expression and Induce DNA Damage in Cell Lines Derived from Pediatric Solid Tumors". International Journal of Molecular Sciences 23, n. 15 (1 agosto 2022): 8549. http://dx.doi.org/10.3390/ijms23158549.

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Anticancer therapy by anthracyclines often leads to the development of multidrug resistance (MDR), with subsequent treatment failure. Thiosemicarbazones have been previously suggested as suitable anthracycline partners due to their ability to overcome drug resistance through dual Pgp-dependent cytotoxicity-inducing effects. Here, we focused on combining anthracyclines (doxorubicin, daunorubicin, and mitoxantrone) and two thiosemicarbazones (DpC and Dp44mT) for treating cell types derived from the most frequent pediatric solid tumors. Our results showed synergistic effects for all combinations of treatments in all tested cell types. Nevertheless, further experiments revealed that this synergism was independent of Pgp expression but rather resulted from impaired DNA repair control leading to cell death via mitotic catastrophe. The downregulation of checkpoint kinase 1 (CHEK1) expression by thiosemicarbazones and the ability of both types of agents to induce double-strand breaks in DNA may explain the Pgp-independent synergism between anthracyclines and thiosemicarbazones. Moreover, the concomitant application of these agents was found to be the most efficient approach, achieving the strongest synergistic effect with lower concentrations of these drugs. Overall, our study identified a new mechanism that offers an avenue for combining thiosemicarbazones with anthracyclines to treat tumors regardless the Pgp status.

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Franco, Vivian I., Jacqueline M. Henkel, Tracie L. Miller e Steven E. Lipshultz. "Cardiovascular Effects in Childhood Cancer Survivors Treated with Anthracyclines". Cardiology Research and Practice 2011 (2011): 1–13. http://dx.doi.org/10.4061/2011/134679.

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Anthracyclines are commonly used to treat childhood leukemias and lymphomas, as well as other malignancies, leading to a growing population of long-term childhood cancer survivors. However, their use is limited by cardiotoxicity, increasing survivors' vulnerability to treatment-related complications that can markedly affect their quality of life. Survivors are more likely to suffer from heart failure, coronary artery disease, and cerebrovascular accidents compared to the general population. The specific mechanisms of anthracycline cardiotoxicity are complex and remain unclear. Hence, determining the factors that may increase susceptibility to cardiotoxicity is of great importance, as is monitoring patients during and after treatment. Additionally, treatment and prevention options, such as limiting cumulative dosage, liposomal anthracyclines, and dexrazoxane, continue to be explored. Here, we review the cardiovascular complications associated with the use of anthracyclines in treating malignancies in children and discuss methods for preventing, screening, and treating such complications in childhood cancer survivors.

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Puzzovivo, Agata, Agnese Maria Fioretti, Carla Minoia, Roberta Villoni, Santa Carbonara, Giusi Graziano, Fabio Pavone, Attilio Guarini e Stefano Oliva. "Echocardiography Monitoring during Anthracycline Administration in Hodgkin and Non-Hodgkin’s Lymphoma: The Tei Index Evaluation". Journal of Personalized Medicine 12, n. 2 (16 febbraio 2022): 290. http://dx.doi.org/10.3390/jpm12020290.

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Anthracyclines are widely employed in lymphoma’s chemotherapy and has been shown to induce heart failure. Echocardiographic parameters of left ventricular (LV) systolic function are usually used to monitor the cardiac side effects during and after anthracyclines treatment. The measurement of theTei index could anticipate the onset of LV dysfunction. The aim of this study was to evaluate the performance of the delta Tei index for the early detection of cardiac toxicity in a prospective population of anthracycline-treated lymphoma patients. Our preliminary data suggest that the Tei index may predict the risk for cardiotoxicity in this subset of patients earlier than LV ejection fraction alteration.

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Angelotti, Austin, Deena Snoke, Rachel Cole, Genevieve Sparagna e Martha Belury. "Characterizing Cardiolipin Species in the Hearts After Anthracycline Administration". Current Developments in Nutrition 5, Supplement_2 (giugno 2021): 934. http://dx.doi.org/10.1093/cdn/nzab050_001.

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Abstract Objectives Anthracyclines damage the heart by binding to the inner mitochondrial membrane phospholipid cardiolipin and promoting mitochondrial dysfunction. Our goal is to characterize how anthracylcines change the fatty acid profile of cardiolipin, and the genes controlling cardiolipin synthesis and remodeling in order to develop dietary strategies to target cardiolipin within damaged hearts. Methods Male C57BL/6J mice were randomized to receive seven IP, anthracycline injections (one week apart) or saline control injections. Six hours after the final injection, mice were euthanized under isoflurane and hearts were collected for mRNA and cardiolipin species analysis. Cardiolipin was measured using liquid chromatography coupled to electrospray ionization mass spectrometry in an API 4000 mass spectrometer (Sciex, Framingham, MA). A student's t-test was used to determine significance between the groups. Results While the amount of tetralinolylcardiolipin (the major cardiolipin species in the heart) was not altered with anthracycline treatment, several other cardiolipin species were significantly increased, including cardiolipin species that contain arachidonic acid and docosahexaenoic acid. In addition we observed a significant decrease in the proportion of monolysocardiolipin species in the heart and a trend towards increased oxidized cardiolipin species given anthracycline treatment. Conclusions Previous studies have shown the fatty acid composition of cardiolipin effects mitochondrial structure and function. Administration of anthracyclines alters cardiolipin species in the heart. Knowing that anthracyclines influences the fatty acid composition of cardiolipin, we can explore dietary interventions that favorably change cardiolipin fatty acid composition, with the goal of preventing anthracycline-induced heart damage by improving mitochondrial function. Funding Sources Funding was provided by NIH R21CA185140, Ohio Agriculture Research and Development Center, the Carol S. Kennedy Professorship, and the Ohio State University Education and Human Ecology Dissertation Research Fellowship.

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Tagawa, Michihito, Genya Shimbo, Akiko Uemura e Kotaro Matsumoto. "Cardiomyopathy in a dog with multicentric lymphoma following treatment with several anthracyclines". Open Veterinary Journal 11, n. 1 (19 marzo 2021): 6–10. http://dx.doi.org/10.4314/ovj.v11i1.2.

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Background: Canine lymphoma is one of the most frequently occurring malignant neoplasms in dogs. Anthracycline-based chemotherapy for the treatment of canine lymphoma is very effective; however, there is not enough evidence for the development of cardiac toxicity using several anthracyclines as chemotherapeutic agents. Case Description: An 8-year-old, castrated, mixed-breed dog was diagnosed with multicentric lymphoma and received multi-agent chemotherapy. Complete remission was achieved, but the patient had a relapse of lymphoma. After third-line chemotherapy with epirubicin, the patient was diagnosed with dilated cardiomyopathy. The total cumulative doses of doxorubicin, mitoxantrone, and epirubicin were 125, 8, and 125 mg/m2, respectively. Although the patient was treated with cardiac drugs and clinically stabilized, the patient had a relapse of lymphoma and died shortly after the diagnosis of cardiomyopathy. Conclusion: The patient was suspected to have anthracycline-induced cardiomyopathy. Further studies are required to establish prevention and management strategies for dogs receiving potentially cardiotoxic therapies, such as anthracyclines.

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Gschwantler-Kaulich, D., A. Fink-Retter, T. Bachrich, M. Ledesma, E. Ruecklinger, E. Kubista e C. F. Singer. "Efficacy of primary systemic chemotherapy regimen containing anthracyclines with/without taxanes in comparison to CMF in women with early breast cancer". Journal of Clinical Oncology 25, n. 18_suppl (20 giugno 2007): 11098. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.11098.

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11098 Background: Neoadjuvant chemotherapy is the treatment of choice for locally-advanced breast cancer and leads to down staging and improved BCT rates. While its efficacy is well established, considerably less is known about the most effective regimen. Methods: We have performed a retrospective analysis of 132 breast cancer patients who had undergone neoadjuvant chemotherapy at our institution. Patients had either received a) anthracyclines (“A”, n=35), b) anthracyclines and taxanes (“AT”, n=55), or c) neither of the two compounds (“NoA/T”, n=42). Clinical response, pathological response and survival were evaluated in each arm. Results: While all three regimen resulted in significant tumor regression, AT was most effective with a mean tumor shrinkage of 39% (ultrasound) and 41% (mammography) (Kruskal-Wallis, p=0.004, and p=0.027). Breast conservation was achieved in 75% by AT, in 49% by A, and in 19% by NoA/T (Kruskal-Wallis, p<0.001). The treatment groups did not differ in respect to pCR (χ2-test, p=0.068), although higher cumulative anthracycline doses were predictive of pCR in multivariate analyses (p=0.022). While the mammographic and not the ultrasound-determined tumor diameter determined whether a woman underwent BCT, only an ultrasound-determined size reduction was predictive for DFS and OS (log rank, p=0.0093, and p=0.044, respectively). Other parameters that affected BCT rates were age (p= 0.003), year of diagnosis (p=<0.001), presence of multifocal disease (p= 0.032) and the cumulative anthracycline dose (p= <0.001). Conclusions: While the combination of anthracyclines and taxanes is most effective in achieving clinical remission and BCT, the cumulative anthracycline dose appears most important for achieving pCR. No significant financial relationships to disclose.

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Dadson, Keith, Oscar Calvillo-Argüelles, Paaladinesh Thavendiranathan e Filio Billia. "Anthracycline-induced cardiomyopathy: cellular and molecular mechanisms". Clinical Science 134, n. 13 (luglio 2020): 1859–85. http://dx.doi.org/10.1042/cs20190653.

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Abstract Despite the known risk of cardiotoxicity, anthracyclines are widely prescribed chemotherapeutic agents. They are broadly characterized as being a robust effector of cellular apoptosis in rapidly proliferating cells through its actions in the nucleus and formation of reactive oxygen species (ROS). And, despite the early use of dexrazoxane, no effective treatment strategy has emerged to prevent the development of cardiomyopathy, despite decades of study, suggesting that much more insight into the underlying mechanism of the development of cardiomyopathy is needed. In this review, we detail the specific intracellular activities of anthracyclines, from the cell membrane to the sarcoplasmic reticulum, and highlight potential therapeutic windows that represent the forefront of research into the underlying causes of anthracycline-induced cardiomyopathy.

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Chong, Wei, Huikun Zhang, Zhifang Guo, Limin Yang, Ying Shao, Xiaoli Liu, Yawen Zhao et al. "Aquaporin 1 promotes sensitivity of anthracycline chemotherapy in breast cancer by inhibiting β-catenin degradation to enhance TopoIIα activity". Cell Death & Differentiation 28, n. 1 (19 agosto 2020): 382–400. http://dx.doi.org/10.1038/s41418-020-00607-9.

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AbstractAnthracyclines are a class of conventional and commonly used frontline chemotherapy drugs to treat breast cancer. However, the anthracycline-based regimens can only reduce breast cancer mortality by 20–30%. Furthermore, there is no appropriate biomarker for predicting responses to this kind of chemotherapy currently. Here we report our findings that may fill this gap by showing the AQP1 (Aquaporin1) protein as a potential response predictor in the anthracycline chemotherapy. We showed that breast cancer patients with a high level of AQP1 expression who underwent the anthracycline treatment had a better clinical outcome relative to those with a low level of AQP1 expression. In the exploration of the underlying mechanisms, we found that the AQP1 and glycogen synthase kinase-3β (GSK3β) competitively interacted with the 12 armadillo repeats of β-catenin, followed by the inhibition of the β-catenin degradation that led to β-catenin’s accumulation in the cytoplasm and nuclear translocation. The nuclear β-catenin interacted with TopoIIα and enhanced TopoIIα’s activity, which resulted in a high sensitivity of breast cancer cells to anthracyclines. We also found, the miR-320a-3p can attenuate the anthracycline’s chemosensitivity by inhibiting the AQP1 expression. Taken together, our findings suggest the efficacy of AQP1 as a response predictor in the anthracycline chemotherapy. The application of our study includes, but is not limited to, facilitating screening of the most appropriate breast cancer patients (who have a high AQP1 expression) for better anthracycline chemotherapy and improved prognosis purposes.

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