Structure-activity relationships of antineoplastic agents in multidrug resistance

Clinical resistance to many antineoplastic agents is a major cause of treatment failure. The well-documented phenomenon addressed as multidrug resistance (MDR) allows cells to withstand exposure to lethal doses of drugs with dissimilar chemical structures, modes of action, and physicochemical proper...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1990-07, Vol.33 (7), p.1914-1919
Main Authors: Selassie, Cynthia D, Hansch, Corwin, Khwaja, Tasneem A
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - pharmacology
Cell Line
Cell Survival - drug effects
Cricetinae
Dactinomycin - pharmacology
Drug Resistance
Leukemia L1210
Mice
Regression Analysis
Structure-Activity Relationship
Tumor Cells, Cultured - cytology
Tumor Cells, Cultured - drug effects
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Summary:Clinical resistance to many antineoplastic agents is a major cause of treatment failure. The well-documented phenomenon addressed as multidrug resistance (MDR) allows cells to withstand exposure to lethal doses of drugs with dissimilar chemical structures, modes of action, and physicochemical properties. In one of the earliest studies on MDR, Biedler and Riehm in an attempt to explain the cross-resistance profile of actinomycin D resistant Chinese hamster cells suggested that molecular weight was an important determinant. Our statistical analysis of their data validates their claim and indeed strongly demonstrates that cross resistance is enhanced by the increased size and hydrophobicity of the antitumor agent. Our preliminary studies with methotrexate-resistant L1210 cells indicates that cross resistance is increased in the case of moderate-sized, hydrophilic drugs. These two studies and others suggest that current chemotherapy regimens may be improved by treating resistant cells with antineoplastic agents displaying physicochemical characteristics opposite to that of the original inducing agent.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00169a014