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Mechanisms by which mammalian cells acquire resistance to drugs that affect microtubule assembly
1Department of Pharmacology, University of Texas Medical School, Houston 77225.
Abstract:
The development of resistance in mammalian cells to toxic drugs is a significant clinical problem, especially in cancer chemotherapy where drug-resistant tumor cells often prove to be refractory to treatment. In this article, we review some of the basic mechanisms of drug resistance from the perspective of a single cell bathed in medium containing the drug. These mechanisms may be categorized according to changes in the cell that affect the ability of the drug to accumulate intracellularly, changes in enzymes that are required for drug toxicity, alterations in trapping of the drug or detoxification of the drug, alterations in binding to an intracellular target, or alterations in cellular processes that compensate for the action of the drug. This latter mechanism is illustrated in some depth by discussing mutants of Chinese hamster ovary cells that are resistant to the effects of drugs that interfere with microtubule assembly.
Insights
Drug resistance in mammalian cells is a major challenge in cancer chemotherapy. This review explores cellular mechanisms, including altered drug accumulation, target interaction, and compensatory pathways, contributing to treatment failure.
Area of Science:
- Cell Biology
- Pharmacology
- Oncology
Background:
- Drug resistance in mammalian cells poses a significant clinical challenge, particularly in cancer chemotherapy.
- Drug-resistant tumor cells frequently exhibit refractoriness to established treatment regimens.
Purpose of the Study:
- To review the fundamental mechanisms underlying cellular drug resistance.
- To categorize these mechanisms based on their impact on intracellular drug levels, target interactions, and cellular compensatory processes.
Main Methods:
- Literature review of basic mechanisms of drug resistance.
- Categorization of resistance mechanisms based on cellular changes affecting drug accumulation, toxicity, trapping, detoxification, target binding, or compensatory pathways.
- In-depth discussion of drug resistance via compensatory mechanisms using Chinese hamster ovary cell mutants resistant to microtubule assembly inhibitors.
Main Results:
- Cellular drug resistance mechanisms can be broadly classified by their effects on intracellular drug concentration, enzymatic activity, drug metabolism, target engagement, and adaptive cellular responses.
- Altered cellular processes that compensate for drug action represent a key resistance mechanism.
- Mutants of Chinese hamster ovary cells demonstrate resistance to drugs targeting microtubule assembly through compensatory pathway alterations.
Conclusions:
- Understanding the diverse mechanisms of drug resistance is crucial for developing effective cancer therapies.
- Targeting compensatory cellular pathways may offer novel strategies to overcome drug resistance in tumors.
- Further research into the molecular basis of drug resistance can inform the design of more potent and less resistance-prone chemotherapeutic agents.