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Structure-activity relationships of antineoplastic agents in multidrug resistance
C D Selassie1, C Hansch, T A Khwaja
1Department of Chemistry, Pomona College, Claremont, California 91711.
Abstract:
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.
Insights
Multidrug resistance (MDR) in cancer therapy can be overcome by selecting drugs with opposite physicochemical properties to the original agent. This strategy enhances treatment efficacy against resistant cancer cells.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Clinical resistance to antineoplastic agents is a significant challenge in cancer treatment.
- Multidrug resistance (MDR) enables cancer cells to survive lethal doses of structurally diverse drugs.
- Previous research suggested molecular weight influences MDR cross-resistance profiles.
Purpose of the Study:
- To statistically analyze the relationship between drug physicochemical properties and MDR cross-resistance.
- To investigate how drug size and hydrophobicity affect antineoplastic agent efficacy in resistant cells.
- To propose improved chemotherapy strategies based on drug property modulation.
Main Methods:
- Statistical analysis of existing data on actinomycin D resistant cells.
- Preliminary studies using methotrexate-resistant L1210 cell lines.
- Evaluation of cross-resistance patterns based on drug size and hydrophobicity.
Main Results:
- Increased size and hydrophobicity of antitumor agents strongly enhance cross-resistance.
- Moderate-sized, hydrophilic drugs increase cross-resistance in specific resistant cell lines.
- Physicochemical properties are critical determinants of MDR cross-resistance.
Conclusions:
- Chemotherapy regimens can be optimized by understanding drug physicochemical properties.
- Treating resistant cells with agents having opposite properties to the inducer may improve outcomes.
- Targeting MDR through drug property selection offers a promising avenue for enhancing cancer treatment efficacy.