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Radiation- and anthracycline-induced cardiac toxicity and the influence of ErbB2 blocking agents.

Seemann I, te Poele JA, Song JY, Hoving S, Russell NS, Stewart FA - Breast Cancer Res. Treat. (2013)

Bottom Line: Inflammatory responses in the irradiated epicardium (CD45+ and F4/80+ cells) were significantly reduced in combination with lapatinib.Trastuzumab did not enhance direct radiation or anthracycline toxicity of cardiomyocytes in vitro.Lapatinib did not enhance the risk of radiation or anthracycline-induced cardiac toxicity in mice up to 40 weeks after treatment, but mitochondrial damage was more severe after doxorubicin combined with lapatinib.

View Article: PubMed Central - PubMed

Affiliation: Division of Biological Stress Response (H3), The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.

ABSTRACT
In Her2-positive breast cancer patients, inhibition of epidermal growth factor receptor 2 (ErbB2)-signaling is often combined with chemotherapy and radiotherapy. The risk of cardiac toxicity after anthracyclines and radiotherapy is recognized, but little is known about increased risk when these treatments are combined with ErbB2 inhibition. This study investigated whether ErbB2 inhibition increased radiation or anthracycline-induced toxicity. In an in vitro study, human cardiomyocytes were treated with irradiation or doxorubicin, alone or in combination with trastuzumab, and evaluated for cell survival and growth. Groups of mice received 0 or 14 Gy to the heart, alone or in combination with lapatinib, or 3 × 4 mg/kg doxorubicin alone or in combination with lapatinib. Mice were evaluated 40 weeks after treatment for cardiac damage. Changes in cardiac function ((99m)Tc-Myoview gated SPECT) were related to histomorphology and microvascular damage. Radiation or doxorubicin-induced cardiomyocyte toxicity (in vitro) were not exacerbated by trastuzumab. Cardiac irradiation of mice decreased microvascular density (MVD) and increased endothelial damage in surviving capillaries (decrease alkaline phosphatase expression and increased von Willebrand factor), but these changes were not exacerbated by lapatinib. Inflammatory responses in the irradiated epicardium (CD45+ and F4/80+ cells) were significantly reduced in combination with lapatinib. Irradiation, doxorubicin, and lapatinib each induced cardiac fibrosis but this was not further enhanced when treatments were combined. At the ultra-structural level, both lapatinib and doxorubicin induced mitochondrial damage, which was enhanced in combined treatments. Lapatinib alone also induced mild changes in cardiac function but this was not enhanced in the combined treatments. Trastuzumab did not enhance direct radiation or anthracycline toxicity of cardiomyocytes in vitro. Lapatinib did not enhance the risk of radiation or anthracycline-induced cardiac toxicity in mice up to 40 weeks after treatment, but mitochondrial damage was more severe after doxorubicin combined with lapatinib.

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Mitochondrial changes in the myocardium after ErbB2 inhibition. Electron microscopic images of the myocardium of mice treated with lapatinib alone or in combination with doxorubicin at 40 weeks after treatment. a Age-matched control (n = 3); cardiomyocytes show organized sarcomeres characterized by parallel myofilaments anchored to Z bands and mitochondria were perfectly aligned and packed. b Doxorubicin treatment alone (n = 3); myofilament arranged regularly and mitochondria were aligned with focal vacuolization (arrow). c Lapatinib treatment alone (n = 3); focal damage per cardiomyocyte. Mitochondrial volume increased, mitochondrial cristae were fuzzy and had a cloudy swollen phenotype (arrow). d Direct lapatinib set up combined with doxorubicin (n = 3); e delayed lapatinib set up combined with doxorubicin (n = 3); disorganized mitochondria, mitochondrial cristae were fuzzy and had a cloudy swollen phenotype (arrow), increased volume of mitochondria. MI mitochondria; MF myofibril; Z z-bands; Dic Discus interculatis
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Fig8: Mitochondrial changes in the myocardium after ErbB2 inhibition. Electron microscopic images of the myocardium of mice treated with lapatinib alone or in combination with doxorubicin at 40 weeks after treatment. a Age-matched control (n = 3); cardiomyocytes show organized sarcomeres characterized by parallel myofilaments anchored to Z bands and mitochondria were perfectly aligned and packed. b Doxorubicin treatment alone (n = 3); myofilament arranged regularly and mitochondria were aligned with focal vacuolization (arrow). c Lapatinib treatment alone (n = 3); focal damage per cardiomyocyte. Mitochondrial volume increased, mitochondrial cristae were fuzzy and had a cloudy swollen phenotype (arrow). d Direct lapatinib set up combined with doxorubicin (n = 3); e delayed lapatinib set up combined with doxorubicin (n = 3); disorganized mitochondria, mitochondrial cristae were fuzzy and had a cloudy swollen phenotype (arrow), increased volume of mitochondria. MI mitochondria; MF myofibril; Z z-bands; Dic Discus interculatis

Mentions: H&E stained sections were semi-quantitatively analyzed for changes in the myocardium and blood vessels. There were only minor changes in the vasculature after irradiation alone or in combination with direct lapatinib. However, when delayed lapatinib was given to irradiated mice there was a trend for increased myocardial and blood vessel damage, including dilation of capillaries, degeneration of coronary arteries, degeneration of the myocardium, and hypertrophy of the myocardium (Fig. 7). No severe changes were detected in Dox-treated mice that survived until 40 weeks. Examination of prematurely sacrificed, sick animals did demonstrate damage but this group comprised only a few mice, sacrificed at various times after treatment, so no semi-quantitative analysis was done. Electron microscopy (EM) analysis indicated small changes in myocyte morphology, like local vacuolization, after Dox or lapatinib treatment alone. Changes were enhanced when Dox was combined with lapatinib, either direct or delayed. Focal damage was seen with degenerative changes in the mitochondria, cloudy-swollen phenotype and disorganized, disrupted Z-bands in some cardiomyocytes, but normal looking mitochondria and Z-bands in adjacent cells (Fig. 8).Fig. 7


Radiation- and anthracycline-induced cardiac toxicity and the influence of ErbB2 blocking agents.

Seemann I, te Poele JA, Song JY, Hoving S, Russell NS, Stewart FA - Breast Cancer Res. Treat. (2013)

Mitochondrial changes in the myocardium after ErbB2 inhibition. Electron microscopic images of the myocardium of mice treated with lapatinib alone or in combination with doxorubicin at 40 weeks after treatment. a Age-matched control (n = 3); cardiomyocytes show organized sarcomeres characterized by parallel myofilaments anchored to Z bands and mitochondria were perfectly aligned and packed. b Doxorubicin treatment alone (n = 3); myofilament arranged regularly and mitochondria were aligned with focal vacuolization (arrow). c Lapatinib treatment alone (n = 3); focal damage per cardiomyocyte. Mitochondrial volume increased, mitochondrial cristae were fuzzy and had a cloudy swollen phenotype (arrow). d Direct lapatinib set up combined with doxorubicin (n = 3); e delayed lapatinib set up combined with doxorubicin (n = 3); disorganized mitochondria, mitochondrial cristae were fuzzy and had a cloudy swollen phenotype (arrow), increased volume of mitochondria. MI mitochondria; MF myofibril; Z z-bands; Dic Discus interculatis
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3824562&req=5

Fig8: Mitochondrial changes in the myocardium after ErbB2 inhibition. Electron microscopic images of the myocardium of mice treated with lapatinib alone or in combination with doxorubicin at 40 weeks after treatment. a Age-matched control (n = 3); cardiomyocytes show organized sarcomeres characterized by parallel myofilaments anchored to Z bands and mitochondria were perfectly aligned and packed. b Doxorubicin treatment alone (n = 3); myofilament arranged regularly and mitochondria were aligned with focal vacuolization (arrow). c Lapatinib treatment alone (n = 3); focal damage per cardiomyocyte. Mitochondrial volume increased, mitochondrial cristae were fuzzy and had a cloudy swollen phenotype (arrow). d Direct lapatinib set up combined with doxorubicin (n = 3); e delayed lapatinib set up combined with doxorubicin (n = 3); disorganized mitochondria, mitochondrial cristae were fuzzy and had a cloudy swollen phenotype (arrow), increased volume of mitochondria. MI mitochondria; MF myofibril; Z z-bands; Dic Discus interculatis
Mentions: H&E stained sections were semi-quantitatively analyzed for changes in the myocardium and blood vessels. There were only minor changes in the vasculature after irradiation alone or in combination with direct lapatinib. However, when delayed lapatinib was given to irradiated mice there was a trend for increased myocardial and blood vessel damage, including dilation of capillaries, degeneration of coronary arteries, degeneration of the myocardium, and hypertrophy of the myocardium (Fig. 7). No severe changes were detected in Dox-treated mice that survived until 40 weeks. Examination of prematurely sacrificed, sick animals did demonstrate damage but this group comprised only a few mice, sacrificed at various times after treatment, so no semi-quantitative analysis was done. Electron microscopy (EM) analysis indicated small changes in myocyte morphology, like local vacuolization, after Dox or lapatinib treatment alone. Changes were enhanced when Dox was combined with lapatinib, either direct or delayed. Focal damage was seen with degenerative changes in the mitochondria, cloudy-swollen phenotype and disorganized, disrupted Z-bands in some cardiomyocytes, but normal looking mitochondria and Z-bands in adjacent cells (Fig. 8).Fig. 7

Bottom Line: Inflammatory responses in the irradiated epicardium (CD45+ and F4/80+ cells) were significantly reduced in combination with lapatinib.Trastuzumab did not enhance direct radiation or anthracycline toxicity of cardiomyocytes in vitro.Lapatinib did not enhance the risk of radiation or anthracycline-induced cardiac toxicity in mice up to 40 weeks after treatment, but mitochondrial damage was more severe after doxorubicin combined with lapatinib.

View Article: PubMed Central - PubMed

Affiliation: Division of Biological Stress Response (H3), The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.

ABSTRACT
In Her2-positive breast cancer patients, inhibition of epidermal growth factor receptor 2 (ErbB2)-signaling is often combined with chemotherapy and radiotherapy. The risk of cardiac toxicity after anthracyclines and radiotherapy is recognized, but little is known about increased risk when these treatments are combined with ErbB2 inhibition. This study investigated whether ErbB2 inhibition increased radiation or anthracycline-induced toxicity. In an in vitro study, human cardiomyocytes were treated with irradiation or doxorubicin, alone or in combination with trastuzumab, and evaluated for cell survival and growth. Groups of mice received 0 or 14 Gy to the heart, alone or in combination with lapatinib, or 3 × 4 mg/kg doxorubicin alone or in combination with lapatinib. Mice were evaluated 40 weeks after treatment for cardiac damage. Changes in cardiac function ((99m)Tc-Myoview gated SPECT) were related to histomorphology and microvascular damage. Radiation or doxorubicin-induced cardiomyocyte toxicity (in vitro) were not exacerbated by trastuzumab. Cardiac irradiation of mice decreased microvascular density (MVD) and increased endothelial damage in surviving capillaries (decrease alkaline phosphatase expression and increased von Willebrand factor), but these changes were not exacerbated by lapatinib. Inflammatory responses in the irradiated epicardium (CD45+ and F4/80+ cells) were significantly reduced in combination with lapatinib. Irradiation, doxorubicin, and lapatinib each induced cardiac fibrosis but this was not further enhanced when treatments were combined. At the ultra-structural level, both lapatinib and doxorubicin induced mitochondrial damage, which was enhanced in combined treatments. Lapatinib alone also induced mild changes in cardiac function but this was not enhanced in the combined treatments. Trastuzumab did not enhance direct radiation or anthracycline toxicity of cardiomyocytes in vitro. Lapatinib did not enhance the risk of radiation or anthracycline-induced cardiac toxicity in mice up to 40 weeks after treatment, but mitochondrial damage was more severe after doxorubicin combined with lapatinib.

Show MeSH
Related in: MedlinePlus