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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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Cardiomyocyte viability after ErbB2 inhibition. Fig a/b: Human cardiomyocytes were treated with doxorubicin (0–250 μg/ml) and trastuzumab (0–10 μg/ml) for 3 days. Cells were then washed (3× with PBS) to remove drugs and evaluated for cell viability directly (2a) or re-incubated with trastuzumab only until evaluation at 14 days (2b). Each symbol represents the mean (±SEM) of three experiments and results are expressed as percentage cell survival. Fig c/d: Human cardiomyocytes were irradiated (0, 2.5, 5, or 10 Gy) and then exposed to trastuzumab (0–10 μg/ml) for 14 days (c) or 21 days (d) before evaluation of cell viability. Each symbol represents the mean (±SEM) of three experiments and results are expressed as percentage cell survival
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Fig2: Cardiomyocyte viability after ErbB2 inhibition. Fig a/b: Human cardiomyocytes were treated with doxorubicin (0–250 μg/ml) and trastuzumab (0–10 μg/ml) for 3 days. Cells were then washed (3× with PBS) to remove drugs and evaluated for cell viability directly (2a) or re-incubated with trastuzumab only until evaluation at 14 days (2b). Each symbol represents the mean (±SEM) of three experiments and results are expressed as percentage cell survival. Fig c/d: Human cardiomyocytes were irradiated (0, 2.5, 5, or 10 Gy) and then exposed to trastuzumab (0–10 μg/ml) for 14 days (c) or 21 days (d) before evaluation of cell viability. Each symbol represents the mean (±SEM) of three experiments and results are expressed as percentage cell survival

Mentions: Exposure of human cardiomyocytes for 3 days to Dox induced a dose-dependent decrease in cell viability. However, combination of Dox with trastuzumab did not further decrease myocyte cell viability (Fig. 2a). When Dox was removed after 3 days and cells were evaluated at 14 days after treatment, cell proliferation was not affected by the presence of trastuzumab. Prior exposure to >0.025 μg/ml Dox inhibited cardiomyocyte growth, but this was independent of trastuzumab exposure (Fig. 2b).Fig. 2


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)

Cardiomyocyte viability after ErbB2 inhibition. Fig a/b: Human cardiomyocytes were treated with doxorubicin (0–250 μg/ml) and trastuzumab (0–10 μg/ml) for 3 days. Cells were then washed (3× with PBS) to remove drugs and evaluated for cell viability directly (2a) or re-incubated with trastuzumab only until evaluation at 14 days (2b). Each symbol represents the mean (±SEM) of three experiments and results are expressed as percentage cell survival. Fig c/d: Human cardiomyocytes were irradiated (0, 2.5, 5, or 10 Gy) and then exposed to trastuzumab (0–10 μg/ml) for 14 days (c) or 21 days (d) before evaluation of cell viability. Each symbol represents the mean (±SEM) of three experiments and results are expressed as percentage cell survival
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig2: Cardiomyocyte viability after ErbB2 inhibition. Fig a/b: Human cardiomyocytes were treated with doxorubicin (0–250 μg/ml) and trastuzumab (0–10 μg/ml) for 3 days. Cells were then washed (3× with PBS) to remove drugs and evaluated for cell viability directly (2a) or re-incubated with trastuzumab only until evaluation at 14 days (2b). Each symbol represents the mean (±SEM) of three experiments and results are expressed as percentage cell survival. Fig c/d: Human cardiomyocytes were irradiated (0, 2.5, 5, or 10 Gy) and then exposed to trastuzumab (0–10 μg/ml) for 14 days (c) or 21 days (d) before evaluation of cell viability. Each symbol represents the mean (±SEM) of three experiments and results are expressed as percentage cell survival
Mentions: Exposure of human cardiomyocytes for 3 days to Dox induced a dose-dependent decrease in cell viability. However, combination of Dox with trastuzumab did not further decrease myocyte cell viability (Fig. 2a). When Dox was removed after 3 days and cells were evaluated at 14 days after treatment, cell proliferation was not affected by the presence of trastuzumab. Prior exposure to >0.025 μg/ml Dox inhibited cardiomyocyte growth, but this was independent of trastuzumab exposure (Fig. 2b).Fig. 2

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