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Unique action determinants of double acting topoisomerase inhibitor, TAS-103

R Okamoto1, H Takano, T Sekikawa

  • 1Department of Biochemistry and Biophysics, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.

International Journal of Oncology
|October 18, 2001
PubMed

Insights

O6-methylguanine-DNA methyltransferase (MGMT) and gamma-glutamylcysteine synthetase (gamma-GCS) influence resistance to TAS-103 chemotherapy. MGMT enhances resistance, while gamma-GCS and glutathione (GSH) reduce it, offering potential therapeutic targets.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Chemotherapeutic resistance is a major challenge in cancer treatment.
  • Topoisomerase inhibitors like TAS-103 are used in cancer therapy.
  • Cellular mechanisms underlying resistance to TAS-103 require further elucidation.

Purpose of the Study:

  • To investigate the roles of O6-methylguanine-DNA methyltransferase (MGMT), gamma-glutamylcysteine synthetase (gamma-GCS), and glutathione (GSH) in mediating resistance to TAS-103.
  • To explore the correlation between the expression levels of these molecules and cellular sensitivity to TAS-103.

Main Methods:

  • Analysis of MGMT, gamma-GCS, and GSH levels in 13 human cancer cell lines.
  • Correlation studies between molecular expression and IC50 values for TAS-103.
  • Pharmacological inhibition of gamma-GCS using buthionine sulphoximine.
  • Inhibition of MGMT using O6-benzyl-guanine and MGMT-antisense transfection.

Main Results:

  • MGMT expression positively correlated with TAS-103 IC50, indicating a role in resistance.
  • Gamma-GCS expression inversely correlated with TAS-103 IC50, suggesting a role in sensitivity.
  • Reduced gamma-GCS and GSH, with increased MGMT, were observed in resistant A549 and DLD cells.
  • Inhibition of gamma-GCS increased TAS-103 resistance, while MGMT inhibition sensitized cells to TAS-103.

Conclusions:

  • MGMT contributes to TAS-103 resistance by potentially decreasing drug activity.
  • Gamma-GCS and GSH appear to play a role in TAS-103 sensitivity.
  • Targeting MGMT or modulating gamma-GCS/GSH pathways may represent novel strategies to overcome TAS-103 resistance in cancer.

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