A microdosing approach for characterizing formation and repair of carboplatin–DNA monoadducts and chemoresistance
International Journal of Cancer December 2, 2010 Paul T. Henderson, Tao Li, Miaoling He et al. 37 citations
Platinum-based drugs like carboplatin kill cancer cells by forming DNA adducts, but measuring these adducts in tumors has been technically difficult. Using ultrasensitive accelerator mass spectrometry, researchers detected carboplatin-DNA monoadducts—precursors to toxic crosslinks—at extremely low levels in six cancer cell lines. The most drug-resistant cells had the fewest monoadducts at all time points over 24 hours. Importantly, microdoses (1/100th the therapeutic concentration) produced nearly identical adduct formation and repair kinetics as full doses, suggesting microdosing could predict treatment effects. Intracellular inactivation and efficient DNA repair, particularly nucleotide excision repair, significantly suppressed monoadduct formation in resistant cells, pointing to mechanisms of chemoresistance.