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Resistance to cytotoxic drugs in DNA mismatch repair-deficient cells

S Aebi1, D Fink, R Gordon

  • 1Department of Medicine and the Cancer Center, University of California at San Diego, La Jolla, California 92093-0812, USA.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|November 17, 1998
PubMed

Insights

Loss of DNA mismatch repair (MMR) proteins like hMSH2 or hMLH1 confers resistance to certain chemotherapy drugs, including cisplatin and etoposide. This highlights MMR

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • DNA mismatch repair (MMR) deficiency is prevalent in various cancers.
  • MMR proteins are crucial for genomic stability and DNA repair.
  • Understanding MMR's role in chemotherapy resistance is vital for treatment strategies.

Purpose of the Study:

  • To investigate the impact of MMR deficiency on cellular sensitivity to diverse chemotherapeutic agents.
  • To determine which DNA damaging agents are recognized by MMR proteins.

Main Methods:

  • Utilized cell lines with proficient and deficient DNA mismatch repair (hMSH2 or hMLH1 loss).
  • Assessed drug sensitivity across a panel of common chemotherapeutic agents.
  • Included known resistant agents (6-thioguanine, N-methyl-N'-nitro-N-nitrosoguanidine) as controls.

Main Results:

  • MMR deficiency resulted in low-level resistance to cisplatin, carboplatin, and etoposide.
  • No significant resistance was observed for melphalan, perfosfamide, 5-fluorouracil, doxorubicin, or paclitaxel.
  • Results were consistent across cell lines deficient in hMSH2 and hMLH1.

Conclusions:

  • DNA mismatch repair proteins likely detect DNA adducts from specific agents like cisplatin and carboplatin.
  • MMR proteins may play a role in recognizing etoposide-induced DNA damage and apoptosis signaling.
  • MMR status influences cellular response to certain DNA-damaging chemotherapies.

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