Gonzalez Yanira, Pokrzywinski Kaytee L, Rosen Elliot T, Mog Steven, Aryal Baikuntha, Chehab Leena M, Vijay Vikrant, Moland Carrie L, Desai Varsha G, Dickey Jennifer S, Rao V Ashutosh
Laboratory of Chemistry, Division of Therapeutic Proteins, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave/Bldg 52/72 Rm 2212, Silver Spring, MD, 20993, USA.
Cancer Chemother Pharmacol. 2015 Sep;76(3):447-59. doi: 10.1007/s00280-015-2786-8. Epub 2015 Jun 25.
Chemotherapy with doxorubicin (Dox) causes dose-limiting cardiotoxicity. We investigated the role that gender has on cardiosensitivity to Dox treatment by evaluating reproductive hormone levels in male, castrated male (c-male), female and ovariectomized female (o-female) adult spontaneously hypertensive rats (SHRs) and expression of mitochondria-related genes in male and female adult SHRs.
SST-2 breast tumor-bearing SHRs were treated with saline, Dox, dexrazoxane (Drz) or both Dox and Drz and monitored for 14 days. Tumor size was used to monitor anticancer activity. Heart weight, cardiac lesion score and serum levels of cardiac troponin T (cTnT) were used to determine cardiotoxicity. Serum estradiol (E2) and testosterone were evaluated using electrochemiluminescence immunoassays. Expression of mitochondria-related genes was profiled in heart by MitoChip array analyses.
Dox significantly reduced tumor volume (±Drz) and increased heart weight in all genders (13-30% vs. control). Higher heart lesion scores were observed in reproductively normal animals (male 2.9, female 2.2) than in hormone-deficient animals (c-male 1.7, o-female 1.9). Lesion score and cTnT inversely correlated with hormone levels. Reduced levels of both sex hormones were observed after Dox treatment. Gene expression analyses of Dox-treated hearts showed significant differential expression of oxidative stress genes in male hearts and apoptotic genes in both male and female hearts.
Our results demonstrate that adult tumor-bearing male SHRs are more cardiosensitive to Dox than female or hormone-deficient animals. We provide evidence to suggest that reproductive hormones negatively regulate or are inhibited by Dox-induced cardiotoxicity and the selective cytotoxic mechanism likely functions through the greater activation of oxidative stress and apoptosis in male SHRs.
阿霉素（Dox）化疗会导致剂量限制性心脏毒性。我们通过评估成年自发性高血压大鼠（SHR）雄性、去势雄性（c - 雄性）、雌性和去卵巢雌性（o - 雌性）的生殖激素水平以及成年雄性和雌性SHR中线粒体相关基因的表达，研究性别对Dox治疗心脏敏感性的影响。
对携带SST - 2乳腺肿瘤的SHR用生理盐水、Dox、右丙亚胺（Drz）或Dox与Drz联合处理，并监测14天。用肿瘤大小监测抗癌活性。用心脏重量、心脏病变评分和心肌肌钙蛋白T（cTnT）血清水平确定心脏毒性。用电化学发光免疫分析法评估血清雌二醇（E2）和睾酮水平。通过MitoChip阵列分析对心脏中线粒体相关基因的表达进行分析。
Dox显著减小了所有性别的肿瘤体积（±Drz），并增加了心脏重量（比对照组增加13 - 30%）。生殖功能正常的动物（雄性2.9，雌性2.2）的心脏病变评分高于激素缺乏的动物（c - 雄性1.7，o - 雌性1.9）。病变评分和cTnT与激素水平呈负相关。Dox治疗后两种性激素水平均降低。对Dox处理的心脏进行基因表达分析显示，雄性心脏中氧化应激基因以及雄性和雌性心脏中凋亡基因均有显著差异表达。
我们的结果表明，成年荷瘤雄性SHR对Dox的心脏敏感性高于雌性或激素缺乏的动物。我们提供的证据表明，生殖激素对Dox诱导的心脏毒性起负调节作用或受其抑制，并且这种选择性细胞毒性机制可能通过雄性SHR中氧化应激和凋亡的更大激活而起作用。
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