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Mechanism of resistance to anthracyclines and vinca alkaloids
Abstract:
Occurrence of cross-resistance between anthracyclines and vinca alkaloids is the rule in experimental tumors with acquired resistance to these drugs. So far, there is no indication that this phenomenon is due to an intracellular mechanism of action common to the two groups of drugs. In nearly all reported studies, acquired experimental resistance and cross-resistance are related to a decreased cellular accumulation of both types of drugs, although other factors also are involved. In Ehrlich ascites tumors, a number of findings at steady-state conditions indicate that the decreased accumulation is dependent on a cellular mechanism for active outward drug transport, which is common to anthracyclines and vinca alkaloids, but changes in inward transport and intracellular binding capacity also contribute. Similar findings have been reported for resistance and cross-resistance in P388 leukemia. Recent results with counteraction of acquired experimental resistance in animal tumors by inhibition of outward drug transport and studies on the effect of different anthracycline derivatives on accumulation of daunomycin in resistant cells are discussed.
Insights
Acquired resistance to anthracyclines and vinca alkaloids in tumors is often linked to decreased drug accumulation. This cross-resistance may stem from a shared cellular mechanism for active outward drug transport.
Area of Science:
- Pharmacology
- Cancer Biology
- Drug Resistance Mechanisms
Background:
- Cross-resistance between anthracyclines and vinca alkaloids is common in experimental tumors with acquired drug resistance.
- This phenomenon is generally not attributed to a shared intracellular mechanism of action between these drug classes.
Purpose of the Study:
- To investigate the mechanisms underlying acquired resistance and cross-resistance to anthracyclines and vinca alkaloids in experimental tumor models.
- To explore the role of cellular drug transport in mediating this resistance.
Main Methods:
- Studies on Ehrlich ascites tumors and P388 leukemia models.
- Analysis of cellular drug accumulation, inward and outward drug transport, and intracellular drug binding.
- Investigation of counteracting resistance by inhibiting outward drug transport.
Main Results:
- Acquired resistance and cross-resistance are primarily associated with decreased cellular accumulation of both drug types.
- A common cellular mechanism for active outward drug transport appears to be a key factor in reduced accumulation.
- Changes in inward transport and intracellular binding capacity also contribute to resistance.
Conclusions:
- Decreased cellular drug accumulation, driven by active outward transport, is a major mechanism for cross-resistance between anthracyclines and vinca alkaloids.
- Targeting outward drug transport presents a potential strategy to overcome acquired resistance in cancer chemotherapy.