Comparative cytotoxicities of various morpholinyl anthracyclines.
A series of quinone- and sugar-modified analogs of adriamycin have been tested for growth inhibition of adriamycin-sensitive (P388/S) and -resistant (P388/ADR) sublines of P388 murine leukemia cells in vitro. P388/ADR is less resistant to analogs of adriamycin containing either a 3'-deamino-3'-(4"-morpholinyl) group, MRA; or a -(3"-cyano-4"-morpholinyl) group, MRA-CN, than to adriamycin. However, MRA-CN was the most potent growth inhibitor of either subline. This potency is reduced by either modification of the quinone unit with a 5-imino substituent or restriction of the cyano-morpholinyl ring by an oxygen bridge to the daunosamine sugar. The calcium antagonist verapamil substantially increases the cytotoxicity of adriamycin to P388/ADR but has no appreciable effect on the cytotoxicity of either MRA or MRA-CN. The results suggest that increased uptake and retention by both MRA and MRA-CN may contribute to their increased cytotoxicity, but that the intense potency of the cyano-morpholinyl analogs must be due to other unique properties of these compounds.
D000818:Animals; D000970:Antineoplastic Agents; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004351:Drug Resistance; D004357:Drug Synergism; D007941:Leukemia P388 / Q000188:drug therapy*; D007942:Leukemia, Experimental / Q000188:drug therapy*; D051379:Mice; D013997:Time Factors; D014700:Verapamil / Q000627:therapeutic use
D000970:Antineoplastic Agents; D004317:Doxorubicin; C038555:3'-deamino-3'-(3-cyano-4-morpholinyl)doxorubicin; D014700:Verapamil