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

Si Si Wang, Maike Zimmermann, Hongyong Zhang, Tzu-Yin Lin, Michael Malfatti, Kurt Haack, Ken W Turteltaub, George D. Cimino, Ralph W deVere White, Chong-Xian Pan, Paul Henderson

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)604-613
Number of pages10
JournalInternational Journal of Cancer
Volume141
Issue number3
DOIs
StatePublished - Aug 1 2017

Fingerprint

Carboplatin
Platinum
Non-Small Cell Lung Carcinoma
Mass Spectrometry
oxaliplatin
Drug Resistance
Cell Line
Pharmaceutical Preparations
Inhibitory Concentration 50
Pharmacokinetics
Cell Culture Techniques
Clinical Trials
DNA
Genomics
Cisplatin
Half-Life
Leukocytes
Therapeutics
Body Weight
Drug Therapy

Keywords

  • accelerator mass spectrometry
  • biomarkers of response
  • diagnostic
  • microdosing
  • non-small cell lung cancer
  • platinum-based chemotherapy
  • predictive diagnostics

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

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, Ken W; Cimino, George D.; deVere White, Ralph W; Pan, Chong-Xian; Henderson, Paul.

In: International Journal of Cancer, Vol. 141, No. 3, 01.08.2017, p. 604-613.

Research output: Contribution to journalArticle

Wang, Si Si ; Zimmermann, Maike ; Zhang, Hongyong ; Lin, Tzu-Yin ; Malfatti, Michael ; Haack, Kurt ; Turteltaub, Ken W ; Cimino, George D. ; deVere White, Ralph W ; Pan, Chong-Xian ; Henderson, Paul. / A diagnostic microdosing approach to investigate platinum sensitivity in non-small cell lung cancer. In: International Journal of Cancer. 2017 ; Vol. 141, No. 3. pp. 604-613.
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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.",
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AU - Malfatti, Michael

AU - Haack, Kurt

AU - Turteltaub, Ken W

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AU - Pan, Chong-Xian

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