A diagnostic microdosing approach to investigate platinum sensitivity in non-small cell lung cancer

The platinum-based drugs cisplatin, carboplatin and oxaliplatin are often used for chemotherapy, but drug resistance is common. The prediction of resistance to these drugs via genomics is a challenging problem since hundreds of genes are involved. A possible alternative is to use mass spectrometry to determine the propensity for cells to form drug-DNA adductsthe pharmacodynamic drug-target complex for this class of drugs. The feasibility of predictive diagnostic microdosing was assessed in non-small cell lung cancer (NSCLC) cell culture and a pilot clinical trial. Accelerator mass spectrometry (AMS) was used to quantify [C-14]carboplatin-DNA monoadduct levels in the cell lines induced by microdoses and therapeutic doses of carboplatin, followed by correlation with carboplatin IC50 values for each cell line. The adduct levels in cell culture experiments were linearly proportional to dose (R-2=0.95, p<0.0001) and correlated with IC50 across all cell lines for microdose and therapeutically relevant carboplatin concentrations (p=0.02 and p=0.01, respectively). A pilot microdosing clinical trial was conducted to define protocols and gather preliminary data. Plasma pharmacokinetics (PK) and [C-14]carboplatin-DNA adducts in white blood cells and tumor tissues from six NSCLC patients were quantified via AMS. The blood plasma half-life of [C-14]carboplatin administered as a microdose was consistent with the known PK of therapeutic dosing. The optimal [C-14]carboplatin formulation for the microdose was 10(7) dpm/kg of body weight and 1% of the therapeutic dose for the total mass of carboplatin. No microdose-associated toxicity was observed in the patients. Additional accruals are required to significantly correlate adduct levels with response. What's new? Platinum-based chemotherapy fills an important role in the treatment of advanced non-small cell lung cancer (NSCLC). Nonetheless, the majority of NSCLC patients do not respond to platinum-based drugs, though they still suffer toxicities. The authors of our study assessed the feasibility of using microdoses (approximately 1/100th the therapeutic dose) of [C-14]carboplatin to predict cisplatin or carboplatin response in NSCLC. The C-14 label allowed for [C-14]carboplatin-DNA adduct detection by accelerator mass spectrometry. Adduct levels correlated with drug cytotoxicity in six NSCLC cell lines. A diagnostic microdosing clinical trial was initiated to establish a useful microdose [C-14]carboplatin formulation and obtain preliminary clinical data.