Abstract |
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.
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Authors | D G Streeter, J S Johl, G R Gordon, J H Peters |
Journal | Cancer chemotherapy and pharmacology
(Cancer Chemother Pharmacol)
Vol. 16
Issue 3
Pg. 247-52
( 1986)
ISSN: 0344-5704 [Print] Germany |
PMID | 3457646
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Antibiotics, Antineoplastic
- Naphthacenes
- Doxorubicin
- NSC 354646
- 3'-deamino-3'-(3-cyano-4-morpholinyl)doxorubicin
- Verapamil
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Topics |
- Animals
- Antibiotics, Antineoplastic
(metabolism)
- Cell Line
- Doxorubicin
(analogs & derivatives, metabolism, pharmacology)
- Drug Resistance
- Leukemia P388
(metabolism)
- Leukemia, Experimental
(metabolism)
- Mice
- Naphthacenes
(metabolism, pharmacology)
- Structure-Activity Relationship
- Verapamil
(pharmacology)
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