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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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Kaplan-Meier estimated of overall survival shown for mice treated with lapatinib alone or in combination with radiation or doxorubicin. Survival data are shown for mice treated with radiation (a) or doxorubicin (b) alone or in combination with direct or delayed with lapatinib. Treatment groups were compared with age-matched controls. *indicates significant differences between treated mice and age matched control groups (p < 0.05; Mann–Whitney U-test)
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Fig3: Kaplan-Meier estimated of overall survival shown for mice treated with lapatinib alone or in combination with radiation or doxorubicin. Survival data are shown for mice treated with radiation (a) or doxorubicin (b) alone or in combination with direct or delayed with lapatinib. Treatment groups were compared with age-matched controls. *indicates significant differences between treated mice and age matched control groups (p < 0.05; Mann–Whitney U-test)

Mentions: Irradiation with 14 Gy alone caused no premature deaths and few deaths occurred in combination with direct (7 %) or delayed lapatinib (12 %). Heart and body weights were slightly lower after irradiation (Fig. 3a and Table S1). There were more unscheduled deaths after treatment with Dox (27 %), especially when combined with lapatinib (36 and 33 % deaths for direct and delayed lapatinib) (Fig. 3b; Table S2). Since the group analyses were done on material from surviving animals only, this probably represents an underestimate of the total toxic effects of Dox. Both heart and body weights were also lower after Dox alone or in combination with lapatinib compared to age-matched control.Fig. 3


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)

Kaplan-Meier estimated of overall survival shown for mice treated with lapatinib alone or in combination with radiation or doxorubicin. Survival data are shown for mice treated with radiation (a) or doxorubicin (b) alone or in combination with direct or delayed with lapatinib. Treatment groups were compared with age-matched controls. *indicates significant differences between treated mice and age matched control groups (p < 0.05; Mann–Whitney U-test)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: Kaplan-Meier estimated of overall survival shown for mice treated with lapatinib alone or in combination with radiation or doxorubicin. Survival data are shown for mice treated with radiation (a) or doxorubicin (b) alone or in combination with direct or delayed with lapatinib. Treatment groups were compared with age-matched controls. *indicates significant differences between treated mice and age matched control groups (p < 0.05; Mann–Whitney U-test)
Mentions: Irradiation with 14 Gy alone caused no premature deaths and few deaths occurred in combination with direct (7 %) or delayed lapatinib (12 %). Heart and body weights were slightly lower after irradiation (Fig. 3a and Table S1). There were more unscheduled deaths after treatment with Dox (27 %), especially when combined with lapatinib (36 and 33 % deaths for direct and delayed lapatinib) (Fig. 3b; Table S2). Since the group analyses were done on material from surviving animals only, this probably represents an underestimate of the total toxic effects of Dox. Both heart and body weights were also lower after Dox alone or in combination with lapatinib compared to age-matched control.Fig. 3

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