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[Pleiotropic resistance associated with topoisomerases]
1Département de biologie, Centre de recherche de Vitry-Alfortville, Vitry-sur-Seine, France.
Abstract:
There are at least two well-characterized mechanism of resistance to Topo I and II inhibitors: modifications of intracellular accumulation and reduced formation of cleavable complexes. Limited drug accumulation is usually due to P-glycoproteinMDR or to Multidrug Resistance associated Protein (MRP). Reduction of Topo I (or II) cleavable complexes not related to drug transport can either be due to decreased enzyme levels or enzyme mutations. For Topo II inhibitors, differential expression of the Topo II isoforms alpha and beta and changes in Topo II phosphorylation may also contribute to resistance. For dual Topo I and II inhibitors, resistance mechanisms are more complex to analyze but may also involve dual Topo I and II alterations. Finally, in a given cell line, several mechanisms are commonly associated in pleiotropic resistance to Topo inhibitors.
Insights
Resistance to Topo I and II inhibitors involves altered drug accumulation and reduced complex formation. Multiple mechanisms often combine, leading to pleiotropic resistance in cancer cells.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Topoisomerase (Topo) I and II inhibitors are crucial in cancer therapy.
- Understanding resistance mechanisms is vital for improving treatment efficacy.
Purpose of the Study:
- To elucidate the multifaceted mechanisms of resistance to Topo I and II inhibitors.
- To analyze how combined resistance pathways impact drug effectiveness.
Main Methods:
- Review of established mechanisms of drug resistance.
- Analysis of intracellular drug accumulation pathways (e.g., P-glycoprotein MDR, MRP).
- Examination of alterations in Topo I/II enzyme levels, mutations, isoforms, and phosphorylation.
Main Results:
- Resistance arises from reduced drug accumulation (via MDR or MRP) or impaired cleavable complex formation.
- Reduced complex formation can stem from decreased enzyme levels or mutations.
- Topo II resistance involves isoform expression (alpha/beta) and phosphorylation.
- Dual inhibitors may face complex, combined resistance mechanisms.
Conclusions:
- Pleiotropic resistance, involving multiple mechanisms, is common in cell lines treated with Topo inhibitors.
- Targeting these diverse resistance pathways is essential for overcoming therapeutic challenges.