A microdosing approach for characterizing formation and repair of carboplatin–DNA monoadducts and chemoresistance

Henderson, Paul; Li, Tao; He, Miaoling; Zhang, Hongyong; Malfatti, Michael; Gandara, David R.; Grimminger, Peter P.; Danenberg, Kathleen D.; Beckett, Laurel A.; White, Ralph W. de Vere; Turteltaub, Kenneth W.; Pan, Chong‐Xian

doi:10.1002/ijc.25814

Cited by 34 publications

(58 citation statements)

References 40 publications

(35 reference statements)

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“…We evaluated the feasibility of a phenotypic approach to predicting response to platinum-based chemotherapy in bladder cancer patients by using diagnostic microdosing and AMS analysis of DNA isolated from PBMC and biopsy samples. The linear correlation between carboplatin-DNA adduct levels induced by microdose and therapeutic dose exposures is consistent with our previous cell culture studies (23). The linearity of the pharmacokinetics between these two drug doses (Fig 1C) can be explained by the fact that carboplatin is an alkylating agent that directly reacts with DNA without the need for metabolic activation or transformation (19).…”

Section: Discussionsupporting

confidence: 91%

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Microdose-Induced Drug–DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice

Zimmermann

Wang

Zhang

et al. 2017

Molecular Cancer Therapeutics

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We report progress on predicting tumor response to platinum-based chemotherapy with a novel mass spectrometry approach. Fourteen bladder cancer patients were administered one diagnostic microdose each of [14C]carboplatin (1% of the therapeutic dose). Carboplatin-DNA adducts were quantified by accelerator mass spectrometry (AMS) in blood and tumor samples collected within 24 hours, and compared to subsequent chemotherapy response. Patients with the highest adduct levels were responders, but not all responders had high adduct levels. Four patient-derived bladder cancer xenograft mouse models were used to test the possibility that another drug in the regimen could cause a response. The mice were dosed with [14C]carboplatin or [14C]gemcitabine and the resulting drug-DNA adduct levels were compared to tumor response to chemotherapy. At least one of the drugs had to induce high drug-DNA adduct levels or create a synergistic increase in overall adducts to prompt a corresponding therapeutic response, demonstrating proof-of-principle for drug-DNA adducts as predictive biomarkers.

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Section: Discussionsupporting

confidence: 91%

“…We previously used AMS to quantify [ 14 C]carboplatin-DNA monoadduct formation in cancer cell lines exposed to microdose-relevant drug concentrations (12, 15, 20-23). The resulting adduct-levels correlated with in vitro carboplatin cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Microdose-Induced Drug–DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice

Zimmermann

Wang

Zhang

et al. 2017

Molecular Cancer Therapeutics

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“…To evaluate the pharmacokinetics of GP-4 in rodents at a microdose and a pharmacological dose, rats (n ϭ 3) were administered a single intravenous dose of 0.01 mg/kg of body weight or 3.0 mg/kg 14 C-labeled GP-4 (specific activities, 353 Ci/mmol and 1.26 Ci/mmol, respectively) formulated in 20% Captisol in 0.05 M methanesulfonic acid, pH 3.5. The use of one microdose concentration and one therapeutic concentration for this study is in accordance with the characteristics of previous microdosing studies as well as with the guidelines set forth by the U.S. Food and Drug Administration (FDA) for microdosing studies (5,7,18,19). Following dose administration, whole-blood samples (approximately 0.3 ml) were collected from each animal via the jugular vein at 0, 0.08, 0.25, 0.5, 1, 2, 4, 8, and 24 h postdose and placed into Microtainer tubes coated with lithium heparin (Becton Dickinson, Franklin Lakes, NJ), and the tubes were placed on ice.…”

Section: Chemicals and Reagentsmentioning

confidence: 87%

Use of Microdosing and Accelerator Mass Spectrometry To Evaluate the Pharmacokinetic Linearity of a Novel Tricyclic GyrB/ParE Inhibitor in Rats

Malfatti

Lao

Ramos

et al. 2014

Antimicrob Agents Chemother

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Determining the pharmacokinetics (PKs) of drug candidates is essential for understanding their biological fate. The ability to obtain human PK information early in the drug development process can help determine if future development is warranted. Microdosing was developed to assess human PKs, at ultra-low doses, early in the drug development process. Microdosing has also been used in animals to confirm PK linearity across subpharmacological and pharmacological dose ranges. The current study assessed the PKs of a novel antimicrobial preclinical drug candidate (GP-4) in rats as a step toward human microdosing studies. Dose proportionality was determined at 3 proposed therapeutic doses (3, 10, and 30 mg/kg of body weight), and PK linearity between a microdose and a pharmacological dose was assessed in Sprague-Dawley rats. Plasma PKs over the 3 pharmacological doses were proportional. Over the 10-fold dose range, the maximum concentration in plasma and area under the curve (AUC) increased 9.5-and 15.8-fold, respectively. PKs from rats dosed with a 14 C-labeled microdose versus a 14 C-labeled pharmacological dose displayed dose linearity. In the animals receiving a microdose and the therapeutically dosed animals, the AUCs from time zero to infinity were 2.6 ng · h/ml and 1,336 ng · h/ml, respectively, and the terminal half-lives were 5.6 h and 1.4 h, respectively. When the AUC values were normalized to a dose of 1.0 mg/kg, the AUC values were 277.5 ng · h/ml for the microdose and 418.2 ng · h/ml for the pharmacological dose. This 1.5-fold difference in AUC following a 300-fold difference in dose is considered linear across the dose range. On the basis of the results, the PKs from the microdosed animals were considered to be predictive of the PKs from the therapeutically dosed animals.T he development of new drugs is a long and costly process, often taking more than 10 years and over $1 billion to get one drug to market (1). The huge cost of new drugs is a consequence of the high failure rate of potential candidates prior to approval. One of the factors contributing to the high attrition rate during development is poor pharmacokinetics (PKs). Poor PK parameters are responsible for up to 40% of drug candidates failing to make it past the first studies in humans (2, 3). The ability to predict complete biodistribution profiles, which include PKs, tissue distribution, and route of elimination, early in the drug development process would provide critical data for decisions about the continued development of a drug lead. These data are also useful for the optimization of dosage regimes, potentiation of therapeutic efficacy, tailoring of drug delivery systems, and evaluation of safety. Early evaluation of these factors in humans would determine if further development is warranted before the initiation of costlier clinical trials.Microdosing is a technique used to assess a compound's in vivo biological fate through the administration of subpharmacological doses of a 14 C-labeled drug candidate that produce virtually no adver...

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“…32 Initial preclinical microdose AMS studies inversely correlated induced drug-DNA adduct level in various cancer cell lines with cell line sensitivity toward the drug. 29, 52, 59 …”

Section: Human Studies Enabled By Amsmentioning

confidence: 99%

Use of Accelerator Mass Spectrometry in Human Health and Molecular Toxicology

Enright¹,

Malfatti²,

Zimmermann

et al. 2016

Chem. Res. Toxicol.

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Accelerator Mass Spectrometry (AMS) has been adopted as a powerful bio-analytical method for human studies in the areas of pharmacology and toxicology. The exquisite sensitivity (10−18 mol) of AMS has facilitated studies of toxins and drugs at environmentally and physiologically relevant concentrations in humans. Such studies include: risk assessment of environmental toxicants, drug candidate selection, absolute bioavailability determination, and more recently, assessment of drug-target binding as a biomarker of response to chemotherapy. Combining AMS with complementary capabilities such as high performance liquid chromatography (HPLC) can maximize data within a single experiment and provide additional insight when assessing drugs and toxins, such as metabolic profiling. Recent advances in the AMS technology at Lawrence Livermore National Laboratory have allowed for direct coupling of AMS with complementary capabilities such as HPLC via a liquid sample moving wire interface, offering greater sensitivity compared to graphite-based analysis therefore, enabling the use of lower 14C and chemical doses, which are imperative for clinical testing. The aim of this review is to highlight the recent efforts in human studies using AMS, including technological advancements and discussion of the continued promise of AMS for innovative clinical based research.

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A microdosing approach for characterizing formation and repair of carboplatin–DNA monoadducts and chemoresistance

Cited by 34 publications

References 40 publications

Microdose-Induced Drug–DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice

Microdose-Induced Drug–DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice

Use of Microdosing and Accelerator Mass Spectrometry To Evaluate the Pharmacokinetic Linearity of a Novel Tricyclic GyrB/ParE Inhibitor in Rats

Use of Accelerator Mass Spectrometry in Human Health and Molecular Toxicology

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