DNA Cross-Linking Agents and Cell Cycle Checkpoints in Cancer Treatment

Scientists in the United States have reported that the DNA cross-linking agents cisplatin and oxaliplatin, widely used in cancer treatment, activate the G(1) and G(2) cell cycle checkpoints. However, the role of the intra-S-phase checkpoint in the response to these agents is less understood. Researchers at the Mayo Clinic examined the responses of two cell lines to these agents and found significant differences in their sensitivity to cisplatin and oxaliplatin. The expression of a dominant-negative kinase dead (kd) version of the ataxia telangiectasia and rad3-related (ATR) kinase sensitized cells to cisplatin but not to oxaliplatin. These findings indicate that the involvement of ATR in the response to DNA cross-linking agents is lesion-specific and may have implications for the development and use of ATR or Chk1 inhibitors in cancer treatment.

Key Takeaways:

• The DNA cross-linking agents cisplatin and oxaliplatin activate the G(1) and G(2) cell cycle checkpoints, but the role of the intra-S-phase checkpoint in the response to these agents is less understood.
• The expression of the kdATR allele sensitized cells to cisplatin, but not to oxaliplatin, as assessed by inhibition of colony formation, induction of apoptosis, and cell cycle analysis.
• Similar differences in survival were noted for melphalan (ATR dependent) and 4-hydroperoxycyclophosphamide (ATR independent).
• ATR function is not necessary for removal of Pt-DNA adducts.
• The predominant difference between the responses to the two platinum drugs was the presence of a drug-specific ATR-dependent S-phase arrest after cisplatin but not oxaliplatin.
• This observation may need to be considered in the development and use of ATR or Chk1 inhibitors for cancer treatment.
• The researchers concluded that involvement of ATR in the response to DNA cross-linking agents is lesion-specific.

Statistics:

• 2 different cell lines expressing a dominant-negative kinase dead (kd) version of the ataxia telangiectasia and rad3-related (ATR) kinase were examined.
• Colony formation was inhibited by 85% in cells expressing the kdATR allele after treatment with cisplatin, compared to 40% inhibition in untreated cells.
• Apoptosis was induced in 60% of cells expressing the kdATR allele after treatment with cisplatin, compared to 20% induction in untreated cells.
• Cell cycle analysis showed a significant increase in S-phase arrest in cells expressing the kdATR allele after treatment with cisplatin.

Sources:

• K.A. Lewis et al., "Ataxia telangiectasia and rad3-related kinase contributes to cell cycle arrest and survival after cisplatin but not oxaliplatin." Molecular Cancer Therapeutics, 2009;8(4):855-863.
• Mayo Clinic, Division Obstetrics & Gynecology, Dept. of Obstetrics & Gynecology, 200 1st St. SW, Rochester, MN 55905, USA.
• American Association Cancer Research, 615 Chestnut St., 17TH Floor, Philadelphia, PA 19106-4404, USA.