Nucleosomes in Serum as a Marker for Cell Death

Holdenrieder, Stefan; Stieber, P.; Bodenmüller, Heinz; Fertig, Georg; Fürst, H.; Schmeller, N.; Untch, Michael; Seidel, D.

doi:10.1515/cclm.2001.095

Cited by 126 publications

(125 citation statements)

References 27 publications

(16 reference statements)

Supporting

Mentioning

117

Contrasting

Unclassified

Order By: Relevance

“…Subsequently, they were stored at Ϫ70°C and analyzed in batches containing all samples of a single patient. The details of the preanalytic handling are described in Holdenrieder et al (17). Nucleosomes were determined by the Cell Death Detection-ELISA plus of Roche Diagnostics (Mannheim, Germany).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Circulating Nucleosomes Predict the Response to Chemotherapy in Patients with Advanced Non–Small Cell Lung Cancer

Holdenrieder¹,

Stieber²,

Pawel³

et al. 2004

Clinical Cancer Research

Self Cite

117

100

View full text Add to dashboard Cite

Purpose:We investigated the potential of circulating, nucleosomal DNA for the early prediction of the efficacy of chemotherapy in patients with advanced lung cancer.Experimental Design: In serum of 212 patients with newly diagnosed non-small cell lung cancer (stages III and IV) undergoing chemotherapy, nucleosomes (ELISA, Roche) were measured at days 1, 3, 5, and 8 of the first cycle and before each new therapeutic cycle. Additionally, carcinoembryonic antigen and cytokeratin 19 fragments (CYFRA 21-1; Elecsys, Roche) were determined before each cycle. The therapeutic success was classified by computed tomography before start of the third cycle according to the World Health Organization criteria.Results: In univariate analysis, responders (patients with remission) showed significantly (P < 0.05) lower values for the area under the curve of days 1 to 8 (AUC 1-8) of nucleosomes, the pretherapeutic baseline values of cycle 2 (BV2) and cycle 3 (BV3) of nucleosomes, and higher decreases of the baseline values from cycle 1 to 2 (BV1-2) and from cycle 1 to 3 (BV1-3) compared with nonresponders (patients with stable or progressive disease). Additionally, CYFRA 21-1 (BV1, BV2, BV3, BV1-2, BV1-3) and carcinoembryonic antigen (BV1-2) discriminated significantly between both groups.In multivariate analysis including all parameters available until end of the first therapeutic cycle, nucleosomes (AUC 1-8), CYFRA 21-1 (BV1), stage, and age were independent predictors of therapy response with nucleosomes (AUC 1-8) having the strongest impact. Conclusion:Circulating nucleosomes in combination with oncological biomarkers are valuable for the early estimation of the efficacy of chemotherapy in patients with lung cancer.

show abstract

Section: Methodsmentioning

confidence: 99%

“…Nucleosomes were determined by the Cell Death Detection-ELISA plus of Roche Diagnostics (Mannheim, Germany). This assay was modified for its use in serum matrix as specified in Holdenrieder et al (17). Nucleosomes were quantified in arbitrary units (AU).…”

Section: Methodsmentioning

confidence: 99%

Circulating Nucleosomes Predict the Response to Chemotherapy in Patients with Advanced Non–Small Cell Lung Cancer

Holdenrieder¹,

Stieber²,

Pawel³

et al. 2004

Clinical Cancer Research

Self Cite

117

100

View full text Add to dashboard Cite

show abstract

“…8,9 Serum samples were analyzed for nDNA [Cell Death Detection ELISA (Roche, Basel, Switzerland)] as previously described. 14 …”

Section: Blood Sampling Processing and Serological Cell Death Enzymmentioning

confidence: 99%

Evaluation of Circulating Tumor Cells and Serological Cell Death Biomarkers in Small Cell Lung Cancer Patients Undergoing Chemotherapy

Hou

Greystoke

Lancashire

et al. 2009

The American Journal of Pathology

211

186

View full text Add to dashboard Cite

Serological cell death biomarkers and circulating tumor cells (CTCs) have potential uses as tools for pharmacodynamic blood-based assays and their subsequent application to early clinical trials. In this study, we evaluated both the expression and clinical significance of CTCs and serological cell death biomarkers in patients with small cell lung cancer. Blood samples from 88 patients were assayed using enzyme-linked immunosorbent assays for various cytokeratin 18 products (eg, M65, cell death, M30, and apoptosis) as well as nucleosomal DNA. CTCs (per 7.5 ml of blood) were quantified using Veridex CellSearch technology. Before therapeutic treatment, cell death biomarkers were elevated in patients compared with controls. CTCs were detected in 86% of patients; additionally, CD56 was detectable in CTCs, confirming their neoplastic origin. M30 levels correlated with the percentage of apoptotic CTCs. M30 , M65 , lactate dehydrogenase , and CTC number were prognostic for patient survival as determined by univariate analysis. Using multivariate analysis , both lactate dehydrogenase and M65 levels remained significant. CTC number fell following chemotherapy , whereas levels of serological cell death biomarkers peaked at 48 hours and fell by day 22 , mirroring the tumor response. A 48-hour rise in nucleosomal DNA and M30 levels was associated with early response and severe toxicity , respectively. Our results provide a rationale to include the use of serological biomark- Small cell lung cancer (SCLC) is initially chemosensitive but invariably relapses with a chemoresistant phenotype.1 A number of molecularly targeted therapies have been evaluated attempting to improve outcome, but none have succeeded to date.2 Ideally, early clinical trials should incorporate validated pharmacodynamic biomarkers, conducted to good clinical laboratory practice, that demonstrate both proof of mechanism (drug hits target) and proof of concept (tumor responds to drug).3 Although possible, serial biopsies are rare in SCLC, and the tissue obtained often insufficient for extensive molecular profiling. Thus, there is a pressing need for blood-based biomarkers that report therapeutic response.Assays of drug-induced cell death are potential proof of concept biomarkers for multiple therapeutics. 4 The M30 Apoptosense and M65 assays (Peviva, Bromma, Sweden) detect cytokeratin (CK) 18, expressed in epithelial but not hematopoietic cells, and released into the blood following cytoskeletal disassembly and degradation during apoptotic and/or necrotic cell death. 5 The M30 antibody recognizes a caspase-cleaved neoepitope of CK18 that is only revealed during apoptosis, whereas the M65 assay detects full length and cleaved forms of CK18 reporting apoptosis and necrosis.6 Nucleosomal DNA (nDNA) results from cleavage of chromatin by apoptotic endonucleases into membrane bound DNA fragments that are phagocytosed by macrophages and sub-

show abstract

“…Действительно, время жизни нуклеосом, введённых внутривенно мышам, сопоставимо со временем жизни циркулирующей плодной ДНК в крови матери [60,61]. Однако прямые доказательства того, что основная часть ДНК опухолевых или [54,62]. Таким образом, полученные в цикле работ данные не позволяют оценить соотношение между упакованной и не упакованной в нуклеосомы ДНК [54,62].…”

Section: состав циркулирующих в крови комплексов внеклеточных днкunclassified

“…Однако прямые доказательства того, что основная часть ДНК опухолевых или [54,62]. Таким образом, полученные в цикле работ данные не позволяют оценить соотношение между упакованной и не упакованной в нуклеосомы ДНК [54,62].…”

Section: состав циркулирующих в крови комплексов внеклеточных днкunclassified

Generation of blood circulating DNA: the sources, peculiarities of circulation and structure

Bryzgunova

Laktionov

2015

BIOMED KHIM

View full text Add to dashboard Cite

Внеклеточные нуклеиновые кислоты (внНК) в циркуляции как здоровых, так и больных людей были впервые описаны в 1948 г., однако оставались без внимания до середины 60-х годов прошлого века. внНК особенно интенсивно исследуются в последние 5 лет. Основное внимание уделяется исследованию внНК как источнику диагностического материала; однако механизмы генерации внеклеточных нуклеиновых кислот, а также механизмы, обеспечивающие их долговременную циркуляцию в кровотоке, однозначно не установлены. По данным одних авторов, основным источником циркулирующих дезоксирибонуклеиновых кислот в крови (цирДНК) являются процессы некроза и апоптоза, другие ссылаются на возможную секрецию нуклеиновых кислот как здоровыми, так и опухолевыми клетками. Известно, что цирДНК могут циркулировать в крови в течение длительного времени, ускользая от действия ДНК-гидролизующих ферментов крови и, по-видимому, находясь в составе надмолекулярных комплексов. В этом обзоре представлены данные разных авторов и приведены доказательства в пользу всех предложенных теорий появления цирДНК, описаны особенности строения цирДНК, а также факторы, влияющие на время циркуляции ДНК в крови.Ключевые слова: циркулирующая ДНК, апоптоз, некроз, активная секреция, ДНКазы, метилирование.

show abstract

Nucleosomes in Serum as a Marker for Cell Death

Cited by 126 publications

References 27 publications

Circulating Nucleosomes Predict the Response to Chemotherapy in Patients with Advanced Non–Small Cell Lung Cancer

Circulating Nucleosomes Predict the Response to Chemotherapy in Patients with Advanced Non–Small Cell Lung Cancer

Evaluation of Circulating Tumor Cells and Serological Cell Death Biomarkers in Small Cell Lung Cancer Patients Undergoing Chemotherapy

Generation of blood circulating DNA: the sources, peculiarities of circulation and structure

Contact Info

Product

Resources

About