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

• Published in: International journal of cancer Vol. 141; no. 3; pp. 604 - 613
• Main Authors: Wang, Si‐Si, Zimmermann, Maike, Zhang, Hongyong, Lin, Tzu‐yin, Malfatti, Michael, Haack, Kurt, Turteltaub, Kenneth W., Cimino, George D., de Vere White, Ralph, Pan, Chong‐xian, Henderson, Paul T.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.08.2017; Wiley
• Subjects: 60 APPLIED LIFE SCIENCES; accelerator mass spectrometry; Adducts; Aged; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; biomarkers of response; Blood cells; Blood plasma; Body weight; Cancer; Cancer therapies; Carbon Radioisotopes - pharmacokinetics; Carboplatin; Carboplatin - administration & dosage; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell culture; Chemotherapy; Cisplatin; Cisplatin - administration & dosage; Clinical trials; Cytotoxicity; Deoxyribonucleic acid; diagnostic; DNA; DNA Adducts; Dose-Response Relationship, Drug; Drug dosages; Drug resistance; Drug Resistance, Neoplasm; Feasibility studies; Female; Follow-Up Studies; Humans; Leukocytes; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Male; Mass Spectrometry; Mass spectroscopy; Medical research; microdosing; Middle Aged; Neoplasm Staging; non-small cell lung cancer; Non-small cell lung carcinoma; Oxaliplatin; Pharmacodynamics; Pharmacokinetics; Pilot Projects; Platinum; platinum-based chemotherapy; predictive diagnostics; Prognosis; Scientific imaging; Sensitivity; Tissue Distribution; Tissues; Toxicity; Transcription; non-small cell lung cancer; platinum-based chemotherapy; biomarkers of response; microdosing; diagnostic; accelerator mass spectrometry; predictive diagnostics
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.30747

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 adducts—the 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 [14C]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 (R2 = 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 [14C]carboplatin‐DNA adducts in white blood cells and tumor tissues from six NSCLC patients were quantified via AMS. The blood plasma half‐life of [14C]carboplatin administered as a microdose was consistent with the known PK of therapeutic dosing. The optimal [14C]carboplatin formulation for the microdose was 107 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 [14C]carboplatin to predict cisplatin or carboplatin response in NSCLC. The 14C label allowed for [14C]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 [14C]carboplatin formulation and obtain preliminary clinical data.