Quantification of Gemcitabine Incorporation into Human DNA by LC/MS/MS as a Surrogate Measure for Target Engagement

Wickremsinhe, Enaksha; Lutzke, Barry S.; Jones, Barry R; Schultz, Gary; Freeman, Angela B.; Pratt, Susan E.; Bones, Atle M.; Ackermann, Bradley L.

doi:10.1021/ac100984h

Cited by 22 publications

(21 citation statements)

References 21 publications

(21 reference statements)

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“…This phenomenon potentially explains the results for two of our responsive patients who had low microdose-induced carboplatin-DNA adducts. To address this issue, we used gemcitabine microdosing in PDX bearing mice, which has only previously been reported in cell culture (47). Our study indeed showed that the levels of gemcitabine incorporated into DNA correlated with the response of PDXs to chemotherapy.…”

Section: Discussionmentioning

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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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: Discussionmentioning

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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“…The amount of the gemcitabine (dFdC), which is a nucleoside analog of deoxycytidine, was measured using a highly sensitive liquid chromatography/mass spectrometric assay that measured the amount of dFdC incorporated into genomic DNA [11]. Peripheral whole blood samples were collected prior to the administration of gemcitabine on study days 1, 8, and 15 and on days 5 and 19.…”

Section: Methodsmentioning

confidence: 99%

Phase I Study of CHK1 Inhibitor LY2603618 in Combination with Gemcitabine in Patients with Solid Tumors

et al. 2016

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Objective: LY2603618, a selective inhibitor of checkpoint kinase 1 (CHK1) and key regulator of the DNA damage checkpoint, may enhance the effects of antimetabolites. This phase I study defined the recommended phase II dose of LY2603618 combined with gemcitabine. Patients and Methods: Patients with advanced/metastatic disease were administered doses of LY2603618 (70-250 mg/m² or flat-fixed doses of 200 or 230 mg) after gemcitabine (1,000 mg/m²). Safety and pharmacokinetics (PK) were assessed. Results: Among the 50 patients enrolled, frequent adverse events possibly related to study drug treatment included fatigue (44%), decreased platelets (42%), decreased neutrophils (32%), nausea (26%), and decreased hemoglobin (20%). Systemic exposure of LY2603618 increased dose dependently, while clearance was relatively dose independent. The mean LY2603618 half-life varied; however, the durations were still suitable for maintaining human exposures while minimizing accumulation. LY2603618 PK were not altered by gemcitabine administration. Plasma exposures that correlate with the maximal pharmacodynamic effect in nonclinical models were achieved for all doses. One patient with non-small cell lung cancer carcinoma achieved a partial response; 22 patients had stable disease. Conclusions: The maximum tolerated dose of LY2603618 combined with gemcitabine was 200 mg/m², but a fixed LY2603618 dose of 230 mg combined with gemcitabine was selected as the recommended phase II dose.

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“…After the DNA had been isolated and completely hydrolyzed, the fluorinated nucleotide (dFdC) was detected using LC/MS-MS (20).…”

Section: Pharmacokineticsmentioning

confidence: 99%

Phase I Study of Oral Gemcitabine Prodrug (LY2334737) Alone and in Combination with Erlotinib in Patients with Advanced Solid Tumors

Koolen

Witteveen

Jansen

et al. 2011

Clinical Cancer Research

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Purpose: LY2334737 is an orally available prodrug of gemcitabine. The objective of this study was to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of daily administration of LY2334737 with or without erlotinib.Experimental Design: Patients with advanced or metastatic cancer were treated with escalating doses of LY2334737 monotherapy or in combination with continuous daily administration of 100 mg erlotinib. LY2334737 was given once daily for 14 days of a 21-day cycle. The study was extended with a bioequivalence trial to investigate a novel LY2334737 drug formulation.Results: A total of 65 patients were treated in this study. The MTD was 40 mg LY2334737. Fatigue was the most frequent DLT for LY2334737 monotherapy (4 patients) followed by elevated transaminase levels (2 patients), both observed at the 40-to 50-mg dose levels. Among the 10 patients in the combination arm, 2 had DLTs at the 40-mg dose level. These were fatigue and elevated liver enzyme levels. The most common adverse events were fatigue (n ¼ 38), nausea (n ¼ 27), vomiting (n ¼ 24), diarrhea (n ¼ 23), anorexia (n ¼ 20), pyrexia (n ¼ 18), and elevated transaminase levels (n ¼ 14). The pharmacokinetics showed dose proportional increase in LY2334737 and gemcitabine exposure. The metabolite 2 0 ,2 0 -difluorodeoxyuridine accumulated with an accumulation index of 4.3 (coefficient of variation: 20%). In one patient, complete response in prostate-specific antigen was observed for 4 cycles, and stable disease was achieved in 22 patients overall. Pharmacokinetic analysis showed that the 2 investigated LY2334737 drug formulations were bioequivalent. Conclusions: LY2334737 displays linear pharmacokinetics and the MTD is 40 mg with or without daily administration of 100 mg erlotinib. Signs of antitumor activity warrant further development.

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Quantification of Gemcitabine Incorporation into Human DNA by LC/MS/MS as a Surrogate Measure for Target Engagement

Cited by 22 publications

References 21 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

Phase I Study of CHK1 Inhibitor LY2603618 in Combination with Gemcitabine in Patients with Solid Tumors

Phase I Study of Oral Gemcitabine Prodrug (LY2334737) Alone and in Combination with Erlotinib in Patients with Advanced Solid Tumors

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