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Updated: Aug 1, 2025
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Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
Published on: December 9, 2015
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Resistance to TOP-1 Inhibitors: Good Old Drugs Still Can Surprise Us
Santosh Kumar1, Michael Y Sherman1
1Department of Molecular Biology, Ariel University, Ariel 40700, Israel.
International Journal of Molecular Sciences
|April 28, 2023
Summary
Irinotecan, a cancer drug, can become less effective due to resistance. A key resistance mechanism involves the loss of DNA topoisomerase I binding sites, impacting treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Irinotecan (SN-38) is a vital anticancer agent targeting DNA topoisomerase I (Top1).
- It induces cancer cell death by creating lethal DNA breaks.
- Rapid secondary resistance significantly limits irinotecan's clinical efficacy.
Purpose of the Study:
- To review major mechanisms of irinotecan resistance.
- To highlight recent advancements in understanding and overcoming this resistance.
- To discuss the clinical implications of resistance mechanisms.
Main Methods:
- Literature review of irinotecan resistance mechanisms.
- Analysis of studies on Top1-DNA interactions and DNA repair pathways.
- Discussion of clinical outcomes and therapeutic strategies.
Main Results:
- Resistance mechanisms involve altered irinotecan metabolism, target protein modification, and Top1 binding site loss.
- DNA repair of Top1-dependent cleavages can eliminate numerous Top1 binding sites, a major resistance factor.
- Understanding these mechanisms is crucial for predicting treatment response.
Conclusions:
- Elucidating irinotecan resistance mechanisms provides insights for developing more effective cancer therapies.
- Strategies to overcome resistance are essential for improving patient outcomes.
- Further research into DNA repair and Top1 interactions can guide novel therapeutic approaches.
Keywords:
DNA damage responseDNA repairchemotherapydose escalationdrug resistanceirinotecantopoisomerase IMore Related Videos
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