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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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Microvascular alterations after ErbB2 inhibition alone or in combination with irradiation. a MVD per unit area expressed as number of microvessels per mm2. b ALP positive tissue areas as % of total tissue. c vWF positive tissue areas as % of total tissue *p < 0.05 compared to age-matched untreated controls. Each value represents the mean (±SEM) for minimal five mice per group. Ctrl control; Lap lapatinib; IR irradiation; IR+lap irradiation combined with lapatinib
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Fig4: Microvascular alterations after ErbB2 inhibition alone or in combination with irradiation. a MVD per unit area expressed as number of microvessels per mm2. b ALP positive tissue areas as % of total tissue. c vWF positive tissue areas as % of total tissue *p < 0.05 compared to age-matched untreated controls. Each value represents the mean (±SEM) for minimal five mice per group. Ctrl control; Lap lapatinib; IR irradiation; IR+lap irradiation combined with lapatinib

Mentions: MVD decreased significantly after 14 Gy radiation alone but the decline was not further enhanced by combination with either direct or delayed lapatinib treatment (Fig. 4a). There were no changes in MVD after Dox treatment alone or in combination with lapatinib (data not shown). Radiation-induced changes in MVD were accompanied by endothelial damage, as shown by a marked decrease in ALP activity (Fig. 4b) and an increased expression of the thrombotic endothelial marker vWF after irradiation alone (Fig. 4c). None of these endothelial changes were more severe after combined treatments with lapatinib then after irradiation alone (Fig. 4b, c). Endothelial damage (ALP) or thrombotic changes in the microvascular (vWF) were not detected in Dox-treated mice (data not shown).Fig. 4


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)

Microvascular alterations after ErbB2 inhibition alone or in combination with irradiation. a MVD per unit area expressed as number of microvessels per mm2. b ALP positive tissue areas as % of total tissue. c vWF positive tissue areas as % of total tissue *p < 0.05 compared to age-matched untreated controls. Each value represents the mean (±SEM) for minimal five mice per group. Ctrl control; Lap lapatinib; IR irradiation; IR+lap irradiation combined with lapatinib
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: Microvascular alterations after ErbB2 inhibition alone or in combination with irradiation. a MVD per unit area expressed as number of microvessels per mm2. b ALP positive tissue areas as % of total tissue. c vWF positive tissue areas as % of total tissue *p < 0.05 compared to age-matched untreated controls. Each value represents the mean (±SEM) for minimal five mice per group. Ctrl control; Lap lapatinib; IR irradiation; IR+lap irradiation combined with lapatinib
Mentions: MVD decreased significantly after 14 Gy radiation alone but the decline was not further enhanced by combination with either direct or delayed lapatinib treatment (Fig. 4a). There were no changes in MVD after Dox treatment alone or in combination with lapatinib (data not shown). Radiation-induced changes in MVD were accompanied by endothelial damage, as shown by a marked decrease in ALP activity (Fig. 4b) and an increased expression of the thrombotic endothelial marker vWF after irradiation alone (Fig. 4c). None of these endothelial changes were more severe after combined treatments with lapatinib then after irradiation alone (Fig. 4b, c). Endothelial damage (ALP) or thrombotic changes in the microvascular (vWF) were not detected in Dox-treated mice (data not shown).Fig. 4

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