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Visualizing and Quantifying Endonuclease-Based Site-Specific DNA Damage
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Visualizing and Quantifying Endonuclease-Based Site-Specific DNA Damage

Published on: August 21, 2021

Mechanisms of tolerance to DNA damaging therapeutic drugs

P Karran1

  • 1Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms, Hertfordshire, EN6 3LD, UK. karran@icrf.icnet.uk

Carcinogenesis
|December 26, 2001
PubMed

Insights

Drug resistance can occur when cells tolerate DNA damage, bypassing cell death. Inactivation of the DNA mismatch repair pathway is linked to this tolerance and may confer multidrug resistance.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Anticancer drugs often induce cytotoxicity by damaging DNA.
  • Drug resistance can arise from mechanisms that repair or tolerate DNA lesions.
  • DNA damage tolerance represents a pathway where cells survive persistent DNA damage.

Purpose of the Study:

  • To explore how DNA mismatch repair (MMR) influences drug resistance.
  • To determine if loss of MMR function confers a multidrug resistance phenotype.

Main Methods:

  • Review of existing literature on DNA damage, drug resistance, and MMR.
  • Analysis of mechanisms linking MMR inactivation to tolerance of DNA damaging agents.

Main Results:

  • Tolerance to certain DNA damaging drugs correlates with MMR pathway inactivation.
  • MMR deficiency is a known mechanism for resistance to methylating agents and 6-thioguanine.
  • Defects in MMR are associated with resistance to a diverse range of DNA-damaging drugs.

Conclusions:

  • Inactivation of the DNA mismatch repair pathway is a key factor in drug tolerance and resistance.
  • Loss of MMR function may contribute to a broad multidrug resistance phenotype, impacting sensitivity to various anticancer agents.

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