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

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.

doi:10.1002/ijc.30747

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

Journal Article · Mon Apr 24 00:00:00 EDT 2017 · International Journal of Cancer

DOI:https://doi.org/10.1002/ijc.30747· OSTI ID:1438672

Wang, Si-Si ^[1]; Zimmermann, Maike ^[2]; Zhang, Hongyong ^[1]; Lin, Tzu-yin ^[1]; Malfatti, Michael ^[3]; Haack, Kurt ^[3]; Turteltaub, Kenneth W. ^[3]; Cimino, George D. ^[4]; de Vere White, Ralph ^[5]; Pan, Chong-xian ^[6]; ^[2]

Univ. of California Davis, Sacramento, CA (United States). Division of Hematology and Oncology. Dept. of Internal Medicine. UC Davis Comprehensive Cancer Center
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)
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Accelerated Medical Diagnostics Incorporated, Berkeley, CA (United States)
Univ. of California Davis, Sacramento, CA (United States). Dept. of Urology
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)

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 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. Finally, additional accruals are required to significantly correlate adduct levels with response.

View Accepted Manuscript (DOE)

Research Organization:: Accelerated Medical Diagnostics Incorporated, Berkeley, CA (United States); Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Univ. of California Davis, Sacramento, CA (United States)

Sponsoring Organization:: LLNL Laboratory Directed Research and Development (LDRD) Program; National Inst. of Health (NIH) (United States); USDOE

Grant/Contract Number:: AC52-07NA27344

OSTI ID:: 1438672

Report Number(s):: LLNL-JRNL--703560

Journal Information:: International Journal of Cancer, Journal Name: International Journal of Cancer Journal Issue: 3 Vol. 141; ISSN 0020-7136

Publisher:: WileyCopyright Statement

Country of Publication:: United States

Language:: English

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Mitochondrion-targeted platinum complexes suppressing lung cancer through multiple pathways involving energy metabolism Zhu, Zhenzhu; Wang, Zenghui; Zhang, Changli Chemical Science, Vol. 10, Issue 10 https://doi.org/10.1039/c8sc04871a	journal	January 2019

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60 APPLIED LIFE SCIENCES
accelerator mass spectrometry
biomarkers of response
diagnostic
microdosing
non-small cell lung cancer
platinum-based chemotherapy
predictive diagnostics

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

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Cited By (2)

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