Cardiac resistance to adriamycin in transgenic mice expressing a rat α-cardiac myosin heavy chain human multiple drug resistance 1 fusion gene
Cardiac resistance to adriamycin in transgenic mice expressing a rat α-cardiac myosin heavy chain human multiple drug resistance 1 fusion gene
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DOI：
10.1089/10430349950017950
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发表时间：
1999-05-20
影响因子：
4.2
通讯作者：
Gordon, JW
中科院分区：
文献类型：
--
作者：
Dell'Acqua, G;Polishchuck, R;Gordon, JW
心脏毒性是限制蒽环类药物在癌症化疗中使用的一个主要因素，多柔比星(阿霉素)治疗的患者经常发生心力衰竭，当他们接受累积剂量超过500 mg/m(2)时，为了建立旨在防止这种毒性作用的基因治疗的小鼠模型，我们培育出了高表达人多药耐药(h-MDR1)基因的转基因小鼠，该基因由大鼠心肌肌球蛋白(αCM)重链基因5‘侧翼区的2.12 kb驱动。两个转基因小鼠系在心肌中高水平表达了转基因。转基因动物和对照动物静脉注射阿霉素，单次剂量为10 mg/kg，累积剂量为30 mg/kg。随后对心脏组织进行的光镜和电子显微镜检查显示，对照组小鼠在两种剂量的转基因动物中都没有出现变性变化，这些结果表明，αCM/h-MDR1转基因在心脏中的表达可以保护小鼠免受阿霉素的毒性影响，并表明如果这种结构有效地应用于心脏基因治疗方案，可能允许在癌症治疗中更积极地使用蒽环类药物。
Cardiac toxicity is a major factor that limits the use of anthracyclines in cancer chemotherapy, Heart failure frequently develops in patients treated with doxorubicin (Adriamycin), when they receive a cumulative dose greater than 500 mg/m(2), To make a mouse model for gene therapy designed to prevent this toxic effect, we have produced transgenic mice overexpressing the human cDNA for the multiple drug resistance (h-mdr1) gene driven by 2.12 kb of the 5' flanking region of the rat alpha-cardiac myosin (alpha CM) heavy chain gene. Two lines of transgenic mice expressed the transgene at a high level in heart muscle. Transgenic and control animals were treated with Adriamycin intravenously at either a single dose of 10 mg/kg or a cumulative dose of 30 mg/kg in three injections. Subsequent light and electron microscopic examination of heart tissue demonstrated degenerative changes in control mice that were absent in transgenic animals at both doses, These results show that expression of the alpha CM/h-mdr1 transgene in heart confers protection from the toxic effect of Adriamycin and suggest that such constructs, if employed effectively in cardiac gene therapy protocols, could allow a more aggressive use of anthracyclines in the treatment of cancer.