A microdosing approach for characterizing formation and repair of carboplatin-DNA monoadducts and chemoresistance

Paul Henderson, Tao Li, Miaoling He, Hongyong Zhang, Michael Malfatti, David R Gandara, Peter P. Grimminger, Kathleen D. Danenberg, Laurel A Beckett, Ralph W deVere White, Ken W Turteltaub, Chong-Xian Pan

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Formation and repair of platinum (Pt)-induced DNA adducts is a critical step in Pt drug-mediated cytotoxicity. Measurement of Pt-DNA adduct kinetics in tumors may be useful for better understanding chemoresistance and therapeutic response. However, this concept has yet to be rigorously tested because of technical challenges in measuring the adducts at low concentrations and consistent access to sufficient tumor biopsy material. Ultrasensitive accelerator mass spectrometry was used to detect [14C]carboplatin-DNA monoadducts at the attomole level, which are the precursors to Pt-DNA crosslink formation, in six cancer cell lines as a proof-of-concept. The most resistant cells had the lowest monoadduct levels at all time points over 24 hr. [ 14C]Carboplatin "microdoses" (1/100th the pharmacologically effective concentration) had nearly identical adduct formation and repair kinetics compared to therapeutically relevant doses, suggesting that the microdosing approach can potentially be used to determine the pharmacological effects of therapeutic treatment. Some of the possible chemoresistance mechanisms were also studied, such as drug uptake/efflux, intracellular inactivation and DNA repair in selected cell lines. Intracellular inactivation and efficient DNA repair each contributed significantly to the suppression of DNA monoadduct formation in the most resistant cell line compared to the most sensitive cell line studied (p < 0.001). Nucleotide excision repair (NER)-deficient and -proficient cells showed substantial differences in carboplatin monoadduct concentrations over 24 hr that likely contributed to chemoresistance. The data support the utility of carboplatin microdosing as a translatable approach for defining carboplatin-DNA monoadduct formation and repair, possibly by NER, which may be useful for characterizing chemoresistance in vivo.

Original languageEnglish (US)
Pages (from-to)1425-1434
Number of pages10
JournalInternational Journal of Cancer
Issue number6
StatePublished - Sep 15 2011


  • accelerator mass spectrometry
  • chemoresistance
  • DNA damage
  • DNA repair
  • microdosing
  • platinum chemotherapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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