Cancer Chemotherapy and Pharmacology

, Volume 69, Issue 3, pp 665–677 | Cite as

Debio 0507 primarily forms diaminocyclohexane-Pt-d(GpG) and -d(ApG) DNA adducts in HCT116 cells

  • C. L. King
  • S. Ramachandran
  • S. G. Chaney
  • L. Collins
  • J. A. Swenberg
  • K. E. deKrafft
  • W. Lin
  • L. Cicurel
  • M. Barbier
Original Article

Abstract

Purpose

To characterize the cellular action mechanism of Debio 0507, we compared the major DNA adducts formed by Debio 0507- and oxaliplatin-treated HCT116 human colon carcinoma cells by a combination of inductively coupled plasma mass spectrometry (ICP-MS) and ultraperformance liquid chromatography mass spectrometry (UPLC-MS/MS).

Methods

HCT116 cells were treated with IC50 doses of Debio 0507 or oxaliplatin for 3 days. Total cellular Pt–DNA adducts were determined by ICP-MS. The DNA was digested, and the major Pt–DNA adducts formed by both drugs were characterized by UPLC/MS/MS essentially as described previously for cisplatin (Baskerville-Abraham et al. in Chem Res Toxicol 22:905–912, 2009).

Results

The Pt level/deoxynucleotide was 7.4/104 for DNA from Debio 0507-treated cells and 5.5/104 for oxaliplatin-treated cells following a 3-day treatment at the IC50 for each drug. UPLC-MS/MS in the positive ion mode confirmed the major Pt–DNA adducts formed by both drugs were dach-Pt-d(GpG) (904.2 m/z → 610 m/z and 904.2 m/z → 459 m/z) and dach-Pt-d(ApG) (888.2 m/z → 594 m/z and 888.2 m/z → 459 m/z).

Conclusions

These data show that the major DNA adducts formed by Debio 0507 are the dach-Pt-d(GpG) and dach-Pt-d(ApG) adducts and at equitoxic doses Debio 0507 and oxaliplatin form similar levels of dach-Pt-d(GpG) and dach-Pt-d(ApG) adducts. This suggests that the action mechanisms of Debio 0507 and oxaliplatin are similar at a cellular level.

Keywords

Debio 0507 Oxaliplatin DNA adducts LC/MS UPLC/MS/MS 

Notes

Acknowledgments

This work was supported by Research Contract Debio 0507-069 from Debiopharm SA (Lausanne, Switzerland) and P30-ES10126 from National Institute of Environmental Health Sciences.

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • C. L. King
    • 1
  • S. Ramachandran
    • 1
  • S. G. Chaney
    • 1
    • 2
    • 4
  • L. Collins
    • 3
  • J. A. Swenberg
    • 3
    • 4
  • K. E. deKrafft
    • 5
  • W. Lin
    • 5
  • L. Cicurel
    • 6
  • M. Barbier
    • 6
  1. 1.Department of Biochemistry and Biophysics, School of MedicineUniversity of North CarolinaChapel HillUSA
  2. 2.Lineberger Comprehensive Cancer CenterUniversity of North CarolinaChapel HillUSA
  3. 3.Department of Environmental Sciences and EngineeringUniversity of North CarolinaChapel HillUSA
  4. 4.Curriculum in Toxicology and Center of Environmental Health and SusceptibilityUniversity of North CarolinaChapel HillUSA
  5. 5.Department of ChemistryUniversity of North CarolinaChapel HillUSA
  6. 6.Debiopharm SALausanneSwitzerland

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