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Cellular resistance to anthracyclines
D Nielsen1, C Maare, T Skovsgaard
1Department of Oncology R, University of Copenhagen, Denmark.
Abstract:
The antracyclines induce multiple intracellular effects; however, inhibition of the nuclear enzyme topoisomerase II (TOPO II) is the main mechanism of action. Resistance to anthracyclines in tumor cells is multifactorial. The main mechanisms are: (1) the classic multidrug resistance (MDR) phenotype, which is due to the presence of P-glycoprotein (PGP) in plasma membrane, that is, a "pump" that can extrude a wide range of anticancer drugs. Membrane-active drugs (e.g., verapamil) have been found in vitro to reverse this phenotype. Most clinical studies including chemosensitizers have, however, been disappointing. (2) Non-PGP-mediated MDR: this phenotype is characterized by expression of other proteins in the plasma membrane which are also able to extrude anticancer drugs. (3) Changes in the intracellular distribution of drug: this mechanism has been demonstrated in several cell lines, most often in combination with PGP or non-PGP-mediated resistance. (4) Glutathione transferases (GST) and detoxification mechanisms: these represent a multigene family of enzymes that conjugate glutathione to chemically reactive groups. Direct evidence for a causative role of GST in anthracycline resistance is missing. (5) Alterations in TOPO II (at-MDR): DNA topoisomerases are involved in several aspects of DNA metabolism, in particular genetic recombination, DNA transcription, and chromosome segregation. Low levels of expression or alterations in TOPO II are associated in vitro with resistance. (6) Increased DNA repair: in several cell lines, an increase in the efficacy of DNA repair has been associated with resistance to doxorubicin (DOX). So far, only classic MDR has been shown to contribute to resistance in clinical conditions, whereas evidence for the other mechanisms of resistance is still missing.
Insights
Anthracyclines fight cancer by inhibiting topoisomerase II (TOPO II). Tumor cells develop resistance through various mechanisms, including drug pumps like P-glycoprotein (PGP), but only PGP-mediated resistance is confirmed clinically.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Anthracyclines are crucial anticancer drugs, primarily acting by inhibiting topoisomerase II (TOPO II).
- Tumor cell resistance to anthracyclines is a significant clinical challenge, often involving multiple cellular mechanisms.
- Understanding these resistance mechanisms is vital for developing more effective cancer therapies.
Purpose of the Study:
- To review and summarize the known mechanisms of anthracycline resistance in tumor cells.
- To differentiate between mechanisms observed in vitro and those clinically relevant.
- To highlight the current understanding of factors contributing to treatment failure.
Main Methods:
- Literature review of studies investigating anthracycline resistance.
- Analysis of in vitro data on various resistance mechanisms.
- Evaluation of clinical trial data on chemosensitizers and resistance.
Main Results:
- Multidrug resistance (MDR) mediated by P-glycoprotein (PGP) is the most clinically established mechanism.
- Other proposed mechanisms include non-PGP efflux pumps, altered drug distribution, glutathione transferase activity, TOPO II alterations, and enhanced DNA repair.
- In vitro studies show evidence for these additional mechanisms, but clinical validation is largely lacking.
Conclusions:
- While multiple resistance mechanisms exist in vitro, only PGP-mediated MDR has been definitively linked to clinical anthracycline resistance.
- Further research is needed to validate the clinical significance of other resistance pathways.
- Targeting confirmed resistance mechanisms may improve therapeutic outcomes in cancer treatment.