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Membrane transport alterations as a mechanism of resistance to anticancer agents
Abstract:
An alteration in membrane transport is one of the most common mechanisms by which tumour cells become resistant to anticancer agents and represents one of the major obstacles in present cancer chemotherapy. A recent emphasis on understanding the mechanisms by which drugs are transported into cells should continue to assist attempts to overcome these problems. Resistance in certain instances can be overcome by modifications in the structure of a drug which increases lipophilicity. These successes have usually been obtained where well defined transport processes are present and specific deletions or modifications in the putative transport proteins are apparent, as in the case of classical antifolates. Simplicity, however, never seems to prevail and recent evidence indicates that cells can prevent transport of lipophilic drugs perhaps by modification of the chemical structure or properties of the plasma membrane, as in the case of trimetrexate. Some alkylating agents are transported by well defined carrier systems; for example, nitrogen mustard enters cells by the choline carrier, and melphalan uses two distinct amino acid carrier mechanisms. For both of these agents, tumour cell resistance is sometimes caused by transport defects. Resistance to antitumour nucleosides may be associated with impaired transport, and this has been demonstrated most clearly for cytarabine and fluorodeoxyuridine. In the case of antitumour antibiotics, although resistance is most often associated with a pleiotropic resistance phenotype in which the rate of drug efflux from the cell is increased, certain cases will be discussed in which resistance may be clearly attributed to defective drug uptake.
Insights
Altered membrane transport mechanisms cause cancer drug resistance, hindering chemotherapy. Understanding drug uptake and efflux is key to overcoming this challenge and improving treatment efficacy.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Altered membrane transport is a primary mechanism of cancer drug resistance, significantly impeding chemotherapy effectiveness.
- Understanding cellular drug transport mechanisms is crucial for developing strategies to overcome treatment resistance.
- Drug resistance can arise from defects in drug uptake or increased drug efflux, affecting various anticancer agents.
Purpose of the Study:
- To review the role of membrane transport alterations in cancer drug resistance.
- To discuss how impaired drug uptake and enhanced efflux contribute to chemotherapy failure.
- To explore strategies for overcoming drug resistance by targeting transport mechanisms.
Main Methods:
- Literature review of studies on cancer cell membrane transport and drug resistance.
- Analysis of specific examples of drug resistance related to transport defects for various anticancer agents.
- Discussion of structure-activity relationships and modifications to enhance drug lipophilicity and cellular uptake.
Main Results:
- Defective drug uptake via specific transporters (e.g., choline, amino acid carriers) contributes to resistance against alkylating agents like nitrogen mustard and melphalan.
- Impaired transport mechanisms are implicated in resistance to antitumour nucleosides, such as cytarabine and fluorodeoxyuridine.
- While increased drug efflux is common for antitumour antibiotics, defective uptake also plays a role in resistance for certain agents.
Conclusions:
- Targeting membrane transport processes offers potential therapeutic strategies to circumvent cancer drug resistance.
- Modifying drug structures to enhance lipophilicity or utilizing specific transporter systems can improve drug delivery and efficacy.
- Further research into the complex interplay of membrane transport and drug resistance is essential for advancing cancer chemotherapy.