title: Debio 0507 primarily forms diaminocyclohexane-Pt-d(GpG) and -d(ApG) DNA adducts in HCT116 cells.
abstract: OBJECTIVE
  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 IC(50) 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 7.4/10(4) for DNA from Debio 0507-treated cells and 5.5/10(4) for oxaliplatin-treated cells following a 3-day treatment at the IC(50) 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.
authors.affiliation: Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina, CB #7260, Genetic Medicine Building, Chapel Hill, NC, 27599-7260, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: King
authors.forename: S
authors.initials: S
authors.lastname: Ramachandran
authors.forename: S G
authors.initials: SG
authors.lastname: Chaney
authors.forename: L
authors.initials: L
authors.lastname: Collins
authors.forename: J A
authors.initials: JA
authors.lastname: Swenberg
authors.forename: K E
authors.initials: KE
authors.lastname: DeKrafft
authors.forename: W
authors.initials: W
authors.lastname: Lin
authors.forename: L
authors.initials: L
authors.lastname: Cicurel
authors.forename: M
authors.initials: M
authors.lastname: Barbier
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018929:Cell Culture Techniques; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism*; D003838:Deoxyadenine Nucleotides / Q000737:chemistry / Q000378:metabolism*; D003849:Deoxyguanosine / Q000737:chemistry / Q000378:metabolism*; D015226:Dinucleoside Phosphates / Q000737:chemistry / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000077150:Oxaliplatin; D053719:Tandem Mass Spectrometry
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; C571459:Debio 0507; D003838:Deoxyadenine Nucleotides; D015226:Dinucleoside Phosphates; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; C034298:deoxyguanylyl-(3'-5')-guanosine; C047743:deoxyadenylyl-(3'-5')-deoxyguanosine; D003849:Deoxyguanosine