Uptake and retention of morpholinyl anthracyclines by adriamycin-sensitive and -resistant P388 cells.
3'-Deamino-3'-(4-morpholinyl)adriamycin (MRA) and 3'-deamino-3'(3-cyano-4-morpholinyl)adriamycin (MRA-CN) were compared with adriamycin (ADR) in ADR-sensitive (P388/S) and -resistant (P388/ADR) murine leukemia cell lines with respect to cytotoxicity and cellular accumulation. MRA is only two- to threefold more cytotoxic to P388/S in culture than ADR, whereas MRA-CN is 500-fold more cytotoxic than ADR to this cell line. Yet both MRA and MRA-CN retain their potency against P388/ADR in spite of a 150-fold decrease in potency for ADR. The observed noncross-resistance of both MRA and MRA-CN in P388/ADR correlates with their increased cellular uptake and retention relative to ADR and the inability of P388/ADR to exclude these analogs as readily as it does ADR. The decreased uptake of MRA and MRA-CN in P388/ADR relative to P388/S (1.5 to 2.0-fold), the increased efflux, and the ability of verapamil to enhance cellular uptake of these analogs in P388/ADR, as it does with ADR, all indicate that the mechanism of ADR-resistance effects ADR and the morpholino analogs in a similar manner but to far different extents. The potent cytotoxicity of MRA-CN appears to be related to strong cellular interactions of the drug with macromolecules that are characterized by its nonextraction from cells by chloroform: methanol or 10 M urea and may therefore represent covalent binding.
Streeter
D G
DG
Johl
J S
JS
Gordon
G R
GR
Peters
J H
JH
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D002460:Cell Line; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D004351:Drug Resistance; D007941:Leukemia P388 / Q000378:metabolism*; D007942:Leukemia, Experimental / Q000378:metabolism*; D051379:Mice; D009279:Naphthacenes / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014700:Verapamil / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D009279:Naphthacenes; D004317:Doxorubicin; C048396:NSC 354646; C038555:3'-deamino-3'-(3-cyano-4-morpholinyl)doxorubicin; D014700:Verapamil