DNA adduct formation is a critical step in platinum-induced cell death. The hypothesis is that there exists a threshold level of carboplatin-DNA adducts above which cells and tumors will respond to the drug, and cellular capacity to attain this threshold can be predicted using subtherapeutic drug �microdoses�. Six non-small cell lung cancer and six bladder cancer cell lines were treated with 1 �M (microdose) or 100 �M (therapeutic dose) carboplatin, but with equal amounts of [14C]carboplatin. Carboplatin-DNA monoadduct levels were quantified by accelerator mass spectrometry (AMS) via measurement of radiocarbon in purified DNA samples. Carboplatin cytotoxicity (IC50 values) was correlated with drug-DNA adduct levels. A pilot Phase 0 trial was initiated to compare microdose-induced carboplatin-DNA monoadduct formation in lung and bladder cancer patients to response to subsequent platinum-based chemotherapy. Nine patients received one microdose (1% of the therapeutic dose) of [14C]carboplatin. DNA monoadduct levels in peripheral blood mononuclear cells and tumor tissues were correlated to tumor response to chemotherapy.   DNA monoadduct levels induced by microdose and therapeutic concentrations of carboplatin in vitro with cell lines were highly linearly proportional (r2 = 0.95, p < 0.001) as measured by AMS, and correlated to the total Pt-DNA adduct levels induced by therapeutic carboplatin (r2 = 0.80, p < 0.001) as measured by ICP-MS.  DNA adduct levels were superior in predicting resistance to carboplatin when compared to the mRNA expression of ERCC1, a DNA repair gene commonly used as a biomarker of resistance to platinum-based chemotherapy. Patients with the highest DNA monoadduct levels responded best to carboplatin-based chemotherapy, although more data is needed to achieve statistical significance. This novel microdosing approach is a feasible strategy for characterizing the capacity for cells in vivo to form and repair carboplatin-DNA adducts prior to the initiation of cytotoxic chemotherapy, and  may enable more personalized treatments.

Phase 0 microdosing trial to determine the feasibility of using drug-DNA adducts as biomarkers of platinum-based drug efficacy

246th National Meeting (2013)

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