Debio 0507 primarily forms diaminocyclohexane-Pt-d(GpG) and -d(ApG) DNA adducts in HCT116 cells
| Autor: | Srinivas Ramachandran, James A. Swenberg, Kathryn E. deKrafft, L. Cicurel, M. Barbier, Stephen G. Chaney, Wenbin Lin, Candice L. King, Leonard B. Collins |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
Organoplatinum Compounds Stereochemistry Cell Culture Techniques Antineoplastic Agents Toxicology Tandem mass spectrometry Article Adduct DNA Adducts chemistry.chemical_compound Deoxyadenine Nucleotides Tandem Mass Spectrometry Liquid chromatography–mass spectrometry Humans Deoxyguanosine Pharmacology (medical) Inductively coupled plasma mass spectrometry Chromatography High Pressure Liquid Pharmacology Chromatography HCT116 Cells digestive system diseases Oxaliplatin Oncology chemistry Cell culture Dinucleoside Phosphates Human colon DNA |
| DOI: | 10.17615/35kx-0525 |
| Popis: | 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).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).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).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. |
| Databáze: | OpenAIRE |
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