Early prediction of therapy response in patients with acute myeloid leukemia by nucleosomal DNA fragments

Mueller, Susanne; Holdenrieder, Stefan; Stieber, P.; Haferlach, Torsten; Schalhorn, Andreas; Braess, Jan; Nagel, Dorothea; Seidel, D.

doi:10.1186/1471-2407-6-143

Cited by 26 publications

(18 citation statements)

References 47 publications

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“…This initial peak during cytotoxic CTx, RTx, and immunotherapy has been found for plasma and serum nucleosomes in breast cancer, 185 cervical cancer, 184 lung cancer, 188−190 colorectal cancer, 191,192 pancreatic cancer, 193 For personal use only. malignancies, and also 194 for plasma EBV-DNA in nasopharyngeal cancer. 187 a. Nucleosomes as indicators of therapy-induced cell death.…”

Section: These Discrepant Results Are Explained By the Heterogeneity mentioning

confidence: 98%

“…As a consequence, the AUC for the first four days of therapy was significantly larger in patients with remission than in non-responsive patients. 194 While in leukemias, malignant cells as therapy targets are present in blood, the situation for solid tumors is quite different: Response to therapy and release of nucleosomes may depend on i) the general tumor cell turnover rate; ii) the extent of tissue and tumor perfusion, which regulates the accessibility of the tumor for cytotoxic drugs as well as the release of cell death products into the circulation; iii) the resistance or susceptibility of cancer cells to cytotoxic therapy; iv) the efficiency of the local immune system in limiting tumor growth; and v) the efficiency of local and plasmatic elimination mechanisms to clear liberated nucleosomes.…”

Section: Early Estimation Of Cancer Treatment Efficacymentioning

confidence: 99%

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Clinical use of circulating nucleosomes

Holdenrieder¹,

Stieber²

2009

Critical Reviews in Clinical Laboratory Sciences

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175

133

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Nucleosomes, complexes of DNA and histone proteins, are released from dying and stressed cells into the blood circulation. Concentrations of circulating nucleosomes in plasma and serum are frequently found to be elevated in various cancers, and also in such acute conditions as stroke, trauma, and sepsis as well as in autoimmune diseases. The first part of this review focuses on the structural and functional properties of nucleosomes, the potential sources of nucleosome release into the circulation, the metabolism of circulating nucleosomes, and their pathophysiological role in disease. It goes on to describe the relevance of circulating nucleosomes in the diagnosis and prognosis of non-malignant conditions such as sepsis, stroke, and autoimmune disease. Finally, it describes the clinical value of nucleosomes in the diagnosis, staging, prognosis, and monitoring of therapy in cancer; in particular, their potential as a new diagnostic tool for the early estimation of response to cytotoxic cancer therapy is emphasized.

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Section: These Discrepant Results Are Explained By the Heterogeneity mentioning

confidence: 98%

Section: Early Estimation Of Cancer Treatment Efficacymentioning

confidence: 99%

Clinical use of circulating nucleosomes

Holdenrieder¹,

Stieber²

2009

Critical Reviews in Clinical Laboratory Sciences

Self Cite

175

133

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“… 81 , 82 In addition, monitoring of extracellular nucleosome levels contributes a lot to the assessment of the response to cytotoxic therapy including chemotherapy and radiotherapy in patients with colorectal, 79 pancreatic, 83 and lung cancer 77 as well as hematologic malignancies. 84 Taken together, serum histones and nucleosomes can indicate a variety of health or disease characteristics and may be useful biomarkers for diseases, especially cancer.…”

Section: Clinical Significance Of Serum Histones and Nucleosomesmentioning

confidence: 99%

Release and activity of histone in diseases

et al. 2014

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Histones and their post-translational modifications have key roles in chromatin remodeling and gene transcription. Besides intranuclear functions, histones act as damage-associated molecular pattern molecules when they are released into the extracellular space. Administration of exogenous histones to animals leads to systemic inflammatory and toxic responses through activating Toll-like receptors and inflammasome pathways. Anti-histone treatment (e.g., neutralizing antibodies, activated protein C, recombinant thrombomodulin, and heparin) protect mice against lethal endotoxemia, sepsis, ischemia/reperfusion injury, trauma, pancreatitis, peritonitis, stroke, coagulation, and thrombosis. In addition, elevated serum histone and nucleosome levels have been implicated in multiple pathophysiological processes and progression of diseases including autoimmune diseases, inflammatory diseases, and cancer. Therefore, extracellular histones could serve as biomarkers and novel therapeutic targets in human diseases.

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“…29,49 This initial peak during therapy has been found for nucleosomes and EBV-DNA by other groups, too. 53,55 Various factors may contribute to these typical courses observed in diverse forms of cancer, such as lung, colorectal, pancreatic, and hematologic malignancies, during chemo-, radio-, and immunotherapy, 29,[56][57][58][59] being either spontaneous and therapy-induced release of nucleosomes or the individual elimination capacity from circulation. Although nucleosomes are cell death products not specifically related to tumor cell death, lung tumor cells have shown to be more susceptible to in vitro radiation, as indicated by a faster and higher release of nucleosomes than from physiological bronchioepithelial cells in the same experiments.…”

Section: Relevance Of Circulating Nucleosomes For Monitoring Of Cancementioning

confidence: 99%

“…In a pilot study of 25 patients with acute myeloid leukemia undergoing induction chemotherapy, the area under the curve (AUC) of the first four days of therapy was significantly larger in patients achieving complete remission when compared with nonresponsive patients. 57 While in hematologic diseases tumor cells as therapy targets are present in blood, the preconditions for solid tumors are quite different. In this context, therapeutic efficacy and release of nucleosomes may depend on (1) tissue and tumor perfusion, which regulates the accessability of the tumor for cytotoxic drugs as well as the liberation of cell death products into circulation; (2) the susceptibility or resistance of cancer cells; (3) the general tumor turnover rate; and finally (4) the efficiency of the local immune and nucleosome elimination systems.…”

Section: Relevance Of Circulating Nucleosomes For Monitoring Of Cancementioning

confidence: 99%

Clinical Relevance of Circulating Nucleosomes in Cancer

Holdenrieder¹,

Nagel²,

Schalhorn³

et al. 2008

Annals of the New York Academy of Sciences

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133

113

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Nucleosomes, complexes of DNA and histone proteins, are released during cell death into the blood circulation. Elevated serum and plasma levels have been found in various forms of cancer, but also in autoimmune diseases and acute situations such as stroke, trauma, and during sepsis. Here, the clinical relevance of circulating nucleosomes for diagnosis, staging, prognosis, and therapeutic monitoring of cancer is reviewed. Several studies have shown that levels of nucleosomes are significantly higher in serum and plasma of cancer patients in comparison to healthy controls. However, because of elevations of nucleosome levels in patients with benign diseases relevant for differential diagnosis, they are not suitable for cancer diagnosis. Concerning tumor staging, nucleosome levels correlate with tumor stage and presence of metastases in gastrointestinal cancer, but not in other tumor types. Prognostic value of circulating nucleosomes is found in lung cancer in univariate analyses, but not in multivariate analyses. Circulating nucleosomes are most informative for the monitoring of cytotoxic therapy. Strongly decreasing levels are mainly found in patients with remission of disease, whereas constantly high or increasing values are associated with progressive disease during chemo- and radiotherapy. In addition, therapy outcome is already indicated by the nucleosomal course during the first week of chemo- and radiotherapy in patients with lung, pancreatic, and colorectal cancer as well as in hematologic malignancies. Despite their non-tumor-specificity, kinetics of nucleosomes are valuable markers for the early estimation of therapeutic efficacy and may be helpful to adapting early cancer therapy in the future.

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Early prediction of therapy response in patients with acute myeloid leukemia by nucleosomal DNA fragments

Abstract: Background: Elevated levels of nucleosomal DNA fragments can be detected in plasma and sera of patients with malignant diseases.

Cited by 26 publications

References 47 publications

Clinical use of circulating nucleosomes

Clinical use of circulating nucleosomes

Release and activity of histone in diseases

Clinical Relevance of Circulating Nucleosomes in Cancer

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