Milano Giuseppina, Raucci Angela, Scopece Alessandro, Daniele Ranaldi, Guerrini Uliano, Sironi Luigi, Cardinale Daniela, Capogrossi Maurizio C, Pompilio Giulio
Laboratory of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino - IRCCS, Milan, Italy.
Laboratory of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino - IRCCS, Milan, Italy.
J Am Soc Echocardiogr. 2014 May;27(5):568-79. doi: 10.1016/j.echo.2014.01.014. Epub 2014 Feb 15.
An increased risk for cardiac dysfunction is reported when the anti-epidermal growth factor receptor type 2 (ErbB2) antibody trastuzumab (Trz) is combined with doxorubicin (Dox) as adjuvant chemotherapy for patients with ErbB2-positive breast cancer. The aim of this study was to develop and characterize a novel mouse model of cardiotoxicity that recapitulates the clinical therapeutic protocols of consecutive cycles of Dox followed by Trz therapy.
Chronic cardiotoxicity was induced in mice by administering six intraperitoneal injections of Dox weekly over a 2-week period (n = 38; cumulative dose, 24 mg/kg), Trz alone (n = 15; cumulative dose, 10 mg/kg), Trz administered 1 week after Dox treatment (n = 35), or an equivalent volume of saline (n = 24).
Echocardiography and pressure-volume analysis indicated that Dox administration was responsible for both left ventricular (LV) and right ventricular (RV) systolic dysfunction and dilatation, further exacerbated by subsequent Trz treatment. Trz alone induced a short down-regulation of LV ErbB2/4 expression associated with reversible LV dysfunction but did not affect receptor expression and RV performance. Dox and Trz in combination decreased the ratio of LV weight to tibia length as well as LV and RV wall thickness compared with Dox treatment. Plasma cardiac troponin I levels and myocardial oxidative stress were higher in mice treated with Dox and Trz than in those treated with Dox alone, while a similar increase of interstitial collagen I deposition was observed in both groups. Trz alone did not affect LV and RV remodeling.
These findings suggest that a combined Dox and Trz regimen provokes a detrimental synergistic global cardiac injury extending to both the LV and RV chambers.
据报道，对于人表皮生长因子受体2（ErbB2）阳性乳腺癌患者，抗表皮生长因子受体2（ErbB2）抗体曲妥珠单抗（Trz）与多柔比星（Dox）联合用作辅助化疗时，心脏功能障碍风险增加。本研究的目的是建立并表征一种新型心脏毒性小鼠模型，该模型概括了连续周期的多柔比星治疗后再进行曲妥珠单抗治疗的临床治疗方案。
通过在2周内每周腹腔注射6次多柔比星（n = 38；累积剂量，24 mg/kg）、单独使用曲妥珠单抗（n = 15；累积剂量，10 mg/kg）、在多柔比星治疗1周后给予曲妥珠单抗（n = 35）或等量生理盐水（n = 24）诱导小鼠慢性心脏毒性。
超声心动图和压力-容积分析表明，多柔比星给药导致左心室（LV）和右心室（RV）收缩功能障碍及扩张，随后的曲妥珠单抗治疗使其进一步加重。单独使用曲妥珠单抗导致左心室ErbB2/4表达短暂下调，伴有可逆性左心室功能障碍，但不影响受体表达和右心室功能。与多柔比星治疗相比，多柔比星和曲妥珠单抗联合使用降低了左心室重量与胫骨长度的比值以及左心室和右心室壁厚度。多柔比星和曲妥珠单抗联合治疗的小鼠血浆心肌肌钙蛋白I水平和心肌氧化应激高于单独使用多柔比星治疗的小鼠，而两组间间质I型胶原沉积均有类似增加。单独使用曲妥珠单抗不影响左心室和右心室重塑。
这些发现表明，多柔比星和曲妥珠单抗联合方案会引发有害的协同性全心损伤，累及左心室和右心室腔。
