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Tumour cell resistance to anthracyclines--a review
Abstract:
Resistance to anthracyclines is the major factor limiting their clinical utility. Laboratory studies using cultured experimental and human tumour cells have indicated that reduced intracellular drug accumulation is one important factor underlying resistance. In some systems this results from enhanced active drug efflux, a process which may be circumvented experimentally, for example by calcium antagonists. A specific glycoprotein which is produced in excess and is inherited has been identified in the cell membrane of certain anthracycline-resistant cells, while gene amplification with the appearance of double-minute chromosomes has been noted in others. Thus it is possible that anthracycline resistance arises following inherited changes in the cell membrane resulting in failure of drug accumulation. However, other possibilities exist, including differences in drug binding, either to the cell membrane or to nuclei, differences in metabolism to the semiquinone free radical, and differences in drug penetration related to tumour morphology. For each human tumour type the factor(s) involved may differ, but sufficient clues now exist to suggest that clinical testing of some of the therapeutic possibilities for circumventing anthracycline resistance may soon be appropriate.
Insights
Anthracycline resistance in cancer is often due to reduced drug accumulation. Strategies to overcome this resistance, like using calcium antagonists, are being explored for clinical trials.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Anthracyclines are vital chemotherapy drugs, but their efficacy is limited by drug resistance.
- Reduced intracellular drug accumulation is a key mechanism of anthracycline resistance.
Purpose of the Study:
- To explore the mechanisms of anthracycline resistance in cancer cells.
- To identify potential therapeutic strategies to circumvent anthracycline resistance.
Main Methods:
- Laboratory studies using cultured experimental and human tumor cells.
- Investigated mechanisms including enhanced drug efflux, genetic alterations, and drug-target interactions.
Main Results:
- Reduced intracellular drug accumulation, often due to enhanced active drug efflux, contributes to resistance.
- Mechanisms identified include specific glycoprotein overproduction, gene amplification (double-minute chromosomes), and potential differences in drug binding or metabolism.
- Inherited changes in the cell membrane may lead to failure of drug accumulation.
Conclusions:
- Anthracycline resistance is multifactorial, involving cellular and molecular changes.
- Therapeutic strategies targeting drug efflux or other resistance mechanisms show promise.
- Clinical trials to test methods for overcoming anthracycline resistance are warranted.