Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer.

Swain, Sandra M.; Whaley, Fredrick S.; Gerber, Miriam C.; Weisberg, Steven R.; York, Martin; Spicer, Darcy; Jones, Stephen E.; Wadler, Scott; Desai, Ajit; Vogel, Charles L.; Speyer, James L.; Mittelman, Abraham; Reddy, Salitha; Pendergrass, Kelly; Vélez-Garciá, E; Ewer, Michael S.; Bianchine, Joseph R.; Gams, Richard A.

doi:10.1200/jco.1997.15.4.1318

Cited by 569 publications

(309 citation statements)

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“…every 3 weeks and were randomized to receive either DZR (500 mg/m 2 or 1000 mg/m 2 ) or placebo. 2,3 There was no maximum dose for doxorubicin, and no patients had received anthracyclines previously. The protocols for Studies 088001 and 088006 were identical.…”

Section: Patient Characteristicsmentioning

confidence: 99%

“…2,3 The results of those studies indicated that DZR provided significant cardioprotection, 2 even if treatment started after a cumulative doxorubicin dose of 300 mg/m 2 had been administered. 3 The 2.2% incidence of doxorubicin-related CHF reported by Von Hoff et al 1 may not have been an accurate reflection of the true incidence of this adverse event.…”

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confidence: 99%

“…Those authors speculated that the incidence may have been underestimated due to low doses of doxorubicin administered to many of the patients, limitation of CHF reporting to investigatorobserved CHF symptoms secondary to doxorubicin, and the "usual limitations" of a retrospective study. 1 To determine whether the incidence of doxorubicininduced CHF is higher than that suggested by Von Hoff et al, we analyzed data from patients in the placebo arms of the 088001 and 088006 breast cancer trials 2,3 together with data from patients in the placebo arm of the 088002 lung carcinoma trial, which was a Phase III study of cyclophosphamide, doxorubicin, and vincristine (CAV), administered with or without DZR, in patients with advanced small cell lung carcinoma. 4 The primary objective of this analysis was to examine the relationship between the cumulative doxorubicin dose and the cumulative probability of developing doxorubicin-related CHF.…”

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confidence: 99%

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Congestive heart failure in patients treated with doxorubicin

Swain

Whaley²,

Ewer

2003

Cancer

1,984

1,256

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BACKGROUNDDoxorubicin is a highly effective and widely used cytotoxic agent with application that is limited by cardiotoxicity related to the cumulative dose of the drug. A large‐scale study that retrospectively evaluated the cardiotoxicity of doxorubicin reported that an estimated 7% of patients developed doxorubicin‐related congestive heart failure (CHF) after a cumulative dose of 550 mg/m2. To assess whether this estimate is reflective of the incidence in the broader clinical oncology setting, the authors evaluated data from three prospective studies to determine both the incidence of doxorubicin‐related CHF and the accumulated dose of doxorubicin at which CHF occurs.METHODSA group of 630 patients who were randomized to a doxorubicin‐plus‐placebo arm of three Phase III studies, two studies in patients with breast carcinoma and one study in patients with small cell lung carcinoma, were included in the analysis.RESULTSThirty‐two of 630 patients had a diagnosis of CHF. Analysis indicated that an estimated cumulative 26% of patients would experience doxorubicin‐related CHF at a cumulative dose of 550 mg/m2. Age appeared to be an important risk factor for doxorubicin‐related CHF after a cumulative dose of 400 mg/m2, with older patients (age > 65 years) showing a greater incidence of CHF compared with younger patients (age ≤ 65 years). In addition, > 50% of the patients who experienced doxorubicin‐related CHF had a reduction < 30% in left ventricular ejection fraction (LVEF) while they were on study.CONCLUSIONSDoxorubicin‐related CHF occurs with greater frequency and at a lower cumulative dose than previously reported. These findings further indicate that LVEF is not an accurate predictor of CHF in patients who receive doxorubicin. Cancer 2003;97:2869–79. © 2003 American Cancer Society.DOI 10.1002/cncr.11407

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Section: Patient Characteristicsmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Congestive heart failure in patients treated with doxorubicin

Swain

Whaley²,

Ewer

2003

Cancer

1,984

1,256

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“…Apoptotic cell fraction (sub-G1) in PI-stained cells was measured by flow cytometry as described previously (Swain et al, 1997;Suresh et al, 2003). In brief, after trypsinisation the cells were resuspended in PI staining solution (50 mM ml À1 PI, 0.1% sodium citrate, 0.1% TritonX-100, 0.1 mg ml À1 Rnase in PBS).…”

Section: Flow Cytometric Analysis Of Pi-stained Cellsmentioning

confidence: 99%

“…Various strategies have been developed to protect against DOX-induced cardiotoxic effects. The majority of these studies concern either metal ion chelators or antioxidants that yielded moderate protective effects (Swain et al, 1997;Kotamraju et al, 2000;Liu et al, 2002;Yamanaka et al, 2003;Oliveira et al, 2004).…”

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Caspase-dependent and -independent suppression of apoptosis by monoHER in Doxorubicin treated cells

et al. 2007

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Doxorubicin (DOX) is an antitumour agent for different types of cancer, but the dose-related cardiotoxicity limits its clinical use. To prevent this side effect we have developed the flavonoid monohydroxyethylrutoside (monoHER), a promising protective agent, which did not interfere with the antitumour activity of DOX. To obtain more insight in the mechanism underlying the selective protective effects of monoHER, we investigated whether monoHER (1 mM) affects DOX-induced apoptosis in neonatal rat cardiac myocytes (NeRCaMs), human endothelial cells (HUVECs) and the ovarian cancer cell lines A2780 and OVCAR-3. DOX-induced cell death was effectively reduced by monoHER in heart, endothelial and A2780 cells. OVCAR-3 cells were highly resistant to DOXinduced apoptosis. Experiments with the caspase-inhibitor zVAD-fmk showed that DOX-induced apoptosis was caspase-dependent in HUVECs and A2780 cells, whereas caspase-independent mechanisms seem to be important in NeRCaMs. MonoHER suppressed DOX-dependent activation of the mitochondrial apoptotic pathway in normal and A2780 cells as illustrated by p53 accumulation and activation of caspase-9 and -3 cleavage. Thus, monoHER acts by suppressing the activation of molecular mechanisms that mediate either caspase-dependent or -independent cell death. In light of the current work and our previous studies, the use of clinically achievable concentrations of monoHER has no influence on the antitumour activity of DOX whereas higher concentrations as used in the present study could influence the antitumour activity of DOX.

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Oncocardiology—Past, Present, and Future

Yeh

Chang

2016

JAMA Cardiol

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IMPORTANCE Oncocardiology is a medical discipline that focuses on the identification, prevention, and treatment of cardiovascular complications related to cancer therapy. This discipline has gained interest from the cardiology community in recent years because of a remarkable increase in the number of cancer survivors and the proliferation of new cancer therapies causing cardiovascular complications, such as hypertension, heart failure, vascular complications, and cardiac arrhythmia. In this review, we provide historical perspectives, highlight new discoveries, and speculate on the opportunity created by merging the research interests and clinical practices of cardiology and oncology. OBSERVATIONS The old paradigm of anthracycline cardiotoxic effects is replaced by new insights that anthracycline targets topoisomerase II β to cause DNA double-strand breaks and a profound change in the transcriptome leading to the generation of reactive oxygen species and the development of mitochondriopathy. Prevention of anthracycline cardiotoxic effects should be based on inhibiting or degrading topoisomerase II β. New challenges were posed by the introduction of trastuzumab and tyrosine kinase inhibitors that revolutionized cancer therapy. The on-target cardiotoxic effects of trastuzumab were owing to a prosurvival benefit of Her2 that binds to neuregulin, whereas the off-target effect of multitargeted tyrosine kinase inhibitors may be mediated by disruption of the vascular endothelial growth factor signaling pathway or the stress-induced angiogenesis. Sensitive imaging techniques, such as global strain, and biomarkers have allowed for early detection of cardiotoxic effects. Early treatment with heart failure medications may be beneficial in preventing the development of late cardiotoxic effects. CONCLUSIONS AND RELEVANCE Close collaboration between cardiologists and oncologists is required to meet the demand of an increasing number of cancer survivors. New insights based on mechanistic studies or genetic discoveries will pave the way for better prevention, diagnosis, and treatment of cancer therapy-induced cardiovascular complications.

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Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer.

Cited by 569 publications

References 24 publications

Congestive heart failure in patients treated with doxorubicin

Congestive heart failure in patients treated with doxorubicin

Caspase-dependent and -independent suppression of apoptosis by monoHER in Doxorubicin treated cells

Oncocardiology—Past, Present, and Future

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