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Title: 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 adducts—the pharmacodynamic drug-target complex for this class of drugs. In this paper, 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 IC 50 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 IC 50 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 viamore » 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 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. Finally, additional accruals are required to significantly correlate adduct levels with response.« less
Authors:
 [1] ;  [2] ;  [1] ;  [1] ;  [3] ;  [3] ;  [3] ;  [4] ;  [5] ;  [6] ; ORCiD logo [2]
  1. Univ. of California Davis, Sacramento, CA (United States). Division of Hematology and Oncology. Dept. of Internal Medicine. UC Davis Comprehensive Cancer Center
  2. Univ. of California Davis, Sacramento, CA (United States). Division of Hematology and Oncology. Dept. of Internal Medicine. UC Davis Comprehensive Cancer Center; Accelerated Medical Diagnostics Incorporated, Berkeley, CA (United States)
  3. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
  4. Accelerated Medical Diagnostics Incorporated, Berkeley, CA (United States)
  5. Univ. of California Davis, Sacramento, CA (United States). Dept. of Urology
  6. Univ. of California Davis, Sacramento, CA (United States). Division of Hematology and Oncology. Dept. of Internal Medicine. UC Davis Comprehensive Cancer Center. Dept. of Urology; VA Northern California Health Care System, Mather, CA (United States)
Publication Date:
Report Number(s):
LLNL-JRNL-703560
Journal ID: ISSN 0020-7136
Grant/Contract Number:
AC52-07NA27344; CA93373; HHSN261201000133C; HHSN261201200048C; P41 RR13461; 2P41GM103483-16
Type:
Accepted Manuscript
Journal Name:
International Journal of Cancer
Additional Journal Information:
Journal Volume: 141; Journal Issue: 3; Journal ID: ISSN 0020-7136
Publisher:
Wiley
Research Org:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Univ. of California Davis, Sacramento, CA (United States); Accelerated Medical Diagnostics Incorporated, Berkeley, CA (United States)
Sponsoring Org:
USDOE; LLNL Laboratory Directed Research and Development (LDRD) Program; National Inst. of Health (NIH) (United States)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; non-small cell lung cancer; platinum-based chemotherapy; diagnostic; microdosing; predictive diagnostics; accelerator mass spectrometry; biomarkers of response
OSTI Identifier:
1438672