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01-03-2012 | Original Article

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

Authors: C. L. King, S. Ramachandran, S. G. Chaney, L. Collins, J. A. Swenberg, K. E. deKrafft, W. Lin, L. Cicurel, M. Barbier

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2012

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.

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Title: Debio 0507 primarily forms diaminocyclohexane-Pt-d(GpG) and -d(ApG) DNA adducts in HCT116 cells
Authors: C. L. King
S. Ramachandran
S. G. Chaney
L. Collins
J. A. Swenberg
K. E. deKrafft
W. Lin
L. Cicurel
M. Barbier
Publication date: 01-03-2012
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 3/2012
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-011-1744-3

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