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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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Related in: MedlinePlus

Schedule overview. Schematic representation of schedules for lapatinib given for 20 weeks in the chow, starting at the time of irradiation or doxorubicin (direct), or starting 20 weeks after irradiation or doxorubicin (delayed)
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Fig1: Schedule overview. Schematic representation of schedules for lapatinib given for 20 weeks in the chow, starting at the time of irradiation or doxorubicin (direct), or starting 20 weeks after irradiation or doxorubicin (delayed)

Mentions: Male C57BL/6 mice, aged 8–12 weeks (Charles River Laboratories, France) were randomly allocated to receive 0 Gy or 14 Gy to the heart, or 4 mg/kg Dox intraperitoneal (i.p.) weekly for 3 weeks. Separate cohorts of animals were included for irradiation or anthracycline combined with lapatinib, as well as age matched controls. Lapatinib (from the Netherlands Cancer Institute pharmacy) was mixed with standard mouse chow to a final concentration of 0.48 g/kg. Assuming consumption of 5 g chow/mouse/day, this is equivalent to 100 mg/kg/day. A pilot study with 100 mg/kg/day given in chow or by oral gavages resulted in the same plasma concentration (mean 946 ng/ml and 909 ng/ml lapatinib after chow diet and oral gavages). Lapatinib diet was either started 7 days before irradiation or Dox (direct schedule) to achieve steady state plasma levels, or delayed until 20 weeks after treatment (Fig. 1). Irradiation was with 250 kV X-rays, operating at 12 mA and filtered with 0.6-mm Copper. The dose rate was 0.94 Gy/min, with a field size of 10.6 × 15 mm (including the whole heart and up to 30 % lung volume); the rest of the mouse was shielded with lead. For irradiation, unanesthetized mice were immobilized in a prone position in acrylic perspex jigs. Each treatment group comprised 10–15 mice (n = 125 in total). Experiments were in agreement with the Dutch law on animal experiments and welfare, and in line with the international Guide for the Care and Use of Laboratory Animals (Eighth edition).Fig. 1


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)

Schedule overview. Schematic representation of schedules for lapatinib given for 20 weeks in the chow, starting at the time of irradiation or doxorubicin (direct), or starting 20 weeks after irradiation or doxorubicin (delayed)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig1: Schedule overview. Schematic representation of schedules for lapatinib given for 20 weeks in the chow, starting at the time of irradiation or doxorubicin (direct), or starting 20 weeks after irradiation or doxorubicin (delayed)
Mentions: Male C57BL/6 mice, aged 8–12 weeks (Charles River Laboratories, France) were randomly allocated to receive 0 Gy or 14 Gy to the heart, or 4 mg/kg Dox intraperitoneal (i.p.) weekly for 3 weeks. Separate cohorts of animals were included for irradiation or anthracycline combined with lapatinib, as well as age matched controls. Lapatinib (from the Netherlands Cancer Institute pharmacy) was mixed with standard mouse chow to a final concentration of 0.48 g/kg. Assuming consumption of 5 g chow/mouse/day, this is equivalent to 100 mg/kg/day. A pilot study with 100 mg/kg/day given in chow or by oral gavages resulted in the same plasma concentration (mean 946 ng/ml and 909 ng/ml lapatinib after chow diet and oral gavages). Lapatinib diet was either started 7 days before irradiation or Dox (direct schedule) to achieve steady state plasma levels, or delayed until 20 weeks after treatment (Fig. 1). Irradiation was with 250 kV X-rays, operating at 12 mA and filtered with 0.6-mm Copper. The dose rate was 0.94 Gy/min, with a field size of 10.6 × 15 mm (including the whole heart and up to 30 % lung volume); the rest of the mouse was shielded with lead. For irradiation, unanesthetized mice were immobilized in a prone position in acrylic perspex jigs. Each treatment group comprised 10–15 mice (n = 125 in total). Experiments were in agreement with the Dutch law on animal experiments and welfare, and in line with the international Guide for the Care and Use of Laboratory Animals (Eighth edition).Fig. 1

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