Microdose-Induced Drug-DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice

Area of Science:

• Oncology
• Pharmacology
• Biochemistry

Background:

• Predicting patient response to platinum-based chemotherapy remains a challenge in bladder cancer treatment.
• Drug-DNA adducts are formed when chemotherapy drugs bind to DNA, potentially influencing treatment efficacy.

Purpose of the Study:

• To investigate the utility of quantifying platinum-DNA adducts as predictive biomarkers for chemotherapy response in bladder cancer.
• To explore the role of specific drugs within a regimen in generating adducts and correlating with tumor response.

Main Methods:

• Fourteen bladder cancer patients received a microdose of [¹⁴C]carboplatin, with subsequent quantification of carboplatin-DNA adducts in blood and tumor samples using accelerator mass spectrometry.
• Patient adduct levels were compared with their response to platinum-based chemotherapy.
• Four patient-derived bladder cancer xenograft mouse models were used to assess the adduct-forming potential and response to [¹⁴C]carboplatin or [¹⁴C]gemcitabine.

Main Results:

• Patients with higher carboplatin-DNA adduct levels were more likely to respond to chemotherapy, though not all responders had high adducts.
• In mouse models, a therapeutic response was observed when at least one drug ([¹⁴C]carboplatin or [¹⁴C]gemcitabine) induced high drug-DNA adducts or a synergistic increase in overall adducts.
• These findings demonstrate the proof-of-principle for drug-DNA adducts as predictive biomarkers.

Conclusions:

• Drug-DNA adduct levels show promise as predictive biomarkers for platinum-based chemotherapy response in bladder cancer.
• The formation of drug-DNA adducts by therapeutic agents is a key factor in determining chemotherapy efficacy.