Dissociation of antitumor potency from anthracycline cardiotoxicity in a doxorubicin analog.
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.
D000818:Animals; D000970:Antineoplastic Agents; D001943:Breast Neoplasms / Q000188:drug therapy; D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D006321:Heart / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D051379:Mice; D009206:Myocardium / Q000201:enzymology; D010051:Ovarian Neoplasms / Q000188:drug therapy; D011247:Pregnancy
D000970:Antineoplastic Agents; D007527:Isoenzymes; D004317:Doxorubicin; C038555:3'-deamino-3'-(3-cyano-4-morpholinyl)doxorubicin; D007770:L-Lactate Dehydrogenase