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Reduced topoisomerase II-mediated DNA cleavage in VP-16 resistant human leukemic cell line

Y Saijo1, K Satoh, Y Tokue

  • 1Department of Internal Medicine, Tohoku University, Sendai, Japan.

Anticancer Research
|January 1, 1991
PubMed

Insights

Drug resistance in human leukemic cells (THP-1/E) to VP-16 was linked to reduced DNA cleavage activity. Topoisomerase II activity was comparable but showed less VP-16-induced DNA damage in resistant cells.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Pharmacology

Background:

  • Drug resistance is a major challenge in cancer chemotherapy.
  • VP-16 (etoposide) is a topoisomerase II inhibitor used in treating various cancers.
  • Understanding resistance mechanisms is crucial for improving treatment efficacy.

Purpose of the Study:

  • To investigate the role of topoisomerase II activity in VP-16 drug resistance.
  • To elucidate the molecular mechanisms underlying VP-16 resistance in the THP-1/E human leukemic cell line.

Main Methods:

  • Comparison of topoisomerase II strand-passing activity in nuclear extracts from sensitive and resistant cell lines.
  • Assessment of VP-16-mediated DNA cleavage using pBR322 DNA and nuclear extracts.
  • Evaluation of VP-16 sensitivity of topoisomerase II activity in both cell types.

Main Results:

  • Strand-passing activity of topoisomerase II was comparable between sensitive and resistant cells.
  • VP-16 equally inhibited strand-passing activity in both cell types.
  • VP-16-mediated DNA cleavage was significantly reduced (one-tenth) in resistant cells compared to sensitive cells.

Conclusions:

  • The resistance of THP-1/E cells to VP-16 is primarily due to reduced DNA cleavage activity mediated by topoisomerase II.
  • This finding highlights a specific mechanism of drug resistance that could be targeted for therapeutic strategies.

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