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Updated: Aug 1, 2025

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
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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
PubMed

Insights

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 I

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