A Diagnostic Microdosing Approach to Investigate Platinum Sensitivity in Non-Small Cell Lung Cancer
Si-si Wang, Maike Zimmermann, Hong-Yong Zhang, Tzu-Yin Lin, Michael Malfatti, Kurt W. Haack, Kenneth W. Turteltaub, George Cimino, Ralph W. de Vere White, C. Pan, Paul T. Henderson
International Journal of Cancer May 15, 2017 DOI: 10.1002/ijc.30747 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Pilot clinical trial with cell culture experiments Peer reviewed |
|---|---|
| Sample size | 6 |
| Population | Non-small cell lung cancer (NSCLC) cell lines and six NSCLC patients |
| Intervention | Carboplatin |
| Dose | 107 dpm/kg of body weight and 1% of the therapeutic dose for the total mass of carboplatin |
| Topics | Microdosing |
| Key findings | Carboplatin-DNA adduct levels measured by accelerator mass spectrometry were linearly proportional to dose in NSCLC cell lines and correlated with carboplatin IC50 at microdose and therapeutic concentrations, suggesting adduct measurement may help predict resistance. In six patients, microdose pharmacokinetics matched therapeutic dosing and no microdose-associated toxicity occurred, but further accrual is needed to correlate adduct levels with response. |
Abstract
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.
Comparable studies
Other non-randomized and open-label trials on microdosing, most cited first.
Citations in the library
Cited by 3
- Phase 0/microdosing approaches: time for mainstream application in drug development? Nature Reviews Drug Discovery September 8, 2020
- Toward Predicting Acute Myeloid Leukemia Patient Response to 7 + 3 Induction Chemotherapy via Diagnostic Microdosing Chemical Research in Toxicology August 28, 2018
- Phase 0 trials/ Intra-Target-Microdosing (ITM) and the lung: a review BMC Pulmonary Medicine September 1, 2024