Dissociation of antitumor potency from anthracycline cardiotoxicity in a doxorubicin analog.
Dissociation of antitumor potency from anthracycline cardiotoxicity in a doxorubicin analog.
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阿霉素类似物的抗肿瘤效力与蒽环类心脏毒性的分离。
DOI：
10.1126/science.4012308
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发表时间：
1985
期刊：
影响因子：
--
通讯作者：
Acton,EM
中科院分区：
文献类型：
--
作者：
Sikic,BI;Ehsan,MN;Harker,WG;Friend,NF;Brown,BW;Newman,RA;Hacker,MP;Acton,EM
对主要抗癌药物多柔比星的新同源物的研究已经产生了一种类似物，其效力大约是多柔比星的1000倍，在治疗剂量水平下无心脏毒性，并且与多柔比星无交叉耐药性。3′-脱氨基-3 ′-（3-氰基-4-吗啉基）多柔比星（MRA-CN）是一种新的蒽环类抗生素，它是通过将多柔比星的3′-氨基引入一个新的氰基吗啉基环中而得到的。在体外观察到对人卵巢癌和乳腺癌的效力显著增加;在胎鼠心脏培养物中未伴随心脏毒性增加。多柔比星和MRA-CN都产生了典型的心脏超微结构和生化变化，但在等摩尔浓度。此外，MRA-CN在选择的人肉瘤细胞系MES-SA的多柔比星耐药变体中与多柔比星没有交叉耐药。因此，通过蒽环结构的这种修饰，抗肿瘤功效与心脏毒性和交叉耐药性分离。
The search for new congeners of the leading anticancer drug doxorubicin has led to an analog that is approximately 1000 times more potent, noncardiotoxic at therapeutic dose levels, and non-cross-resistant with doxorubicin. The new anthracycline, 3′-deamino-3′-(3-cyano-4-morpholinyl)doxorubicin (MRA-CN), is produced by incorporation of the 3′ amino group of doxorubicin in a new cyanomorpholinyl ring. The marked increase in potency was observed against human ovarian and breast carcinomas in vitro; it was not accompanied by an increase in cardiotoxicity in fetal mouse heart cultures. Doxorubicin and MRA-CN both produced typical cardiac ultrastructural and biochemical changes, but at equimolar concentrations. In addition, MRA-CN was not cross-resistant with doxorubicin in a variant of the human sarcoma cell line MES-SA selected for resistance to doxorubicin. Thus antitumor efficacy was dissociated from both cardiotoxicity and cross-resistance by this modification of anthracycline structure.