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Topoisomerase I inhibitors: selectivity and cellular resistance
Yves Pommier1, Philippe Pourquier, Yoshimasa Urasaki
1Laboratory of Molecular Pharmacology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Abstract:
Topoisomerase I (top1) inhibitors (camptothecins and other structurally diverse compounds) are effective and promising anticancer agents. Determinants of selectivity toward cancer cells and resistance are multifactorial. These factors can be separated in three groups. The first is related to alterations in drug distribution and metabolism. The second group includes both quantitative and qualitative (mutations) differences in top I. The third group includes resistance and sensitivity factors downstream from the cleavage complexes. They include DNA repair, cell cycle checkpoints and apoptosis, and are probably key to the relative selectivity of camptothecins toward cancer cells and to clinical resistance. Copyright 1999 Harcourt Publishers Ltd.
Insights
Topoisomerase I (top1) inhibitors show promise as anticancer drugs. Their effectiveness and cancer cell selectivity are influenced by drug metabolism, topoisomerase I levels and mutations, and DNA repair pathways.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Topoisomerase I (top1) inhibitors, including camptothecins, are vital anticancer agents.
- Understanding factors influencing their efficacy and resistance is crucial for cancer treatment.
Purpose of the Study:
- To investigate the multifactorial determinants of selectivity and resistance to topoisomerase I inhibitors in cancer cells.
Main Methods:
- Categorization of resistance and sensitivity factors into three main groups.
- Analysis of drug distribution, metabolism, and topoisomerase I alterations (quantity and mutations).
- Examination of downstream factors including DNA repair, cell cycle checkpoints, and apoptosis.
Main Results:
- Drug distribution and metabolism significantly impact topoisomerase I inhibitor efficacy.
- Alterations in topoisomerase I quantity and mutations are key determinants of resistance.
- Downstream cellular processes like DNA repair, cell cycle control, and apoptosis play a critical role in drug selectivity and clinical resistance.
Conclusions:
- The selectivity of topoisomerase I inhibitors, particularly camptothecins, toward cancer cells is complex.
- Clinical resistance to these agents is multifactorial, involving drug-related, target-related, and downstream cellular pathway alterations.