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Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
A diagnostic microdosing approach to investigate platinum sensitivity in non-small cell lung cancer
Si-Si Wang1, Maike Zimmermann1,2, Hongyong Zhang1
1Division of Hematology and Oncology, Department of Internal Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA.
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 [14 C]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 [14 C]carboplatin-DNA adducts in white blood cells and tumor tissues from six NSCLC patients were quantified via AMS. The blood plasma half-life of [14 C]carboplatin administered as a microdose was consistent with the known PK of therapeutic dosing. The optimal [14 C]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.
Insights
Predicting chemotherapy drug resistance using platinum-based drugs like carboplatin is challenging. Measuring platinum-DNA adducts via microdosing shows promise for predicting drug response in non-small cell lung cancer (NSCLC).
Area of Science:
- Pharmacology and Toxicology
- Oncology
- Analytical Chemistry
Background:
- Platinum-based chemotherapy drugs (cisplatin, carboplatin, oxaliplatin) are vital but face common drug resistance issues.
- Genomic prediction of resistance is complex due to the involvement of numerous genes.
- Drug-DNA adduct formation is the key pharmacodynamic event for this drug class.
Purpose of the Study:
- To assess the feasibility of predictive diagnostic microdosing for platinum-based chemotherapy resistance.
- To evaluate the utility of quantifying platinum-DNA adducts as a biomarker for drug response.
- To establish protocols and gather preliminary data for a clinical microdosing trial in non-small cell lung cancer (NSCLC).
Main Methods:
- Accelerator Mass Spectrometry (AMS) was used to quantify [14C]carboplatin-DNA monoadduct levels.
- Experiments were conducted in NSCLC cell cultures and a pilot clinical trial involving NSCLC patients.
- Adduct levels were correlated with drug sensitivity (IC50 values) in cell lines and pharmacokinetic parameters in patients.
Main Results:
- In cell cultures, [14C]carboplatin-DNA adduct levels were dose-proportional (R2 = 0.95, p < 0.0001).
- Adduct levels correlated significantly with carboplatin IC50 values across cell lines (p = 0.02 for microdose, p = 0.01 for therapeutic dose).
- Pilot clinical trial showed [14C]carboplatin microdosing PK was consistent with therapeutic doses, with no observed toxicity. Optimal microdose formulation identified.
Conclusions:
- Microdosing combined with AMS quantification of platinum-DNA adducts is a feasible approach for predicting carboplatin response in NSCLC.
- This pharmacodynamic biomarker approach offers a potential alternative to complex genomic predictions for drug resistance.
- Further clinical accrual is necessary to establish a significant correlation between adduct levels and treatment response.
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