Decitabine

Daskalakis, Michael; Blagitko-Dorfs, Nadja; Hackanson, Björn

doi:10.1007/978-3-642-01222-8_10

Cited by 39 publications

(35 citation statements)

References 133 publications

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“…High levels of DNMT1 expression have been reported in cancer patients who are not responsive to chemotherapy (26). DAC incorporated into DNA covalently binds to DNMT1, leading to the reduction of available DNMT1 protein in cells, which in turn results in DNA demethylation and expression of methylation-silenced genes (28,29). In the present study, we demonstrated that DAC decreased DNMT1 protein expression levels, which was consistent with previous findings.…”

Section: Discussionsupporting

confidence: 92%

Palliative chemotherapy followed by methylation inhibitor in high-risk acute myeloid leukemia: An in vitro and clinical study

Ding

Wang

Jiang

et al. 2015

Molecular and Clinical Oncology

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Abstract. Decitabine (5-aza-2'-deoxycytidine; DAC) is a well-tolerated alternative to aggressive chemotherapy for leukemia, which induces differentiation and apoptosis of leukemic cells as a DNA hypomethylating agent. The aim of the present study was to investigate the feasibility of DAC sequentially combined with chemotherapy to reverse drug resistance. HL-60/ADR multidrug-resistant leukemia cells cultured in 96-well plates were pretreated with DAC for 72 h; varying concentrations of aclacinomycin (ACLA) were then added to the wells, cell proliferation was tested using the Cell Counting Kit-8 assay, and DNA methyltransferase 1 (DNMT1) protein expression was detected by western blot analysis. Furthermore, we analyzed the therapeutic efficacy in 7 patients with high-risk acute myeloid leukemia (AML) receiving induction therapy with DAC sequentially combined with cytarabine, ACLA and granulocyte-colony stimulating factor (CAG regimen). The proliferation inhibition rate of HL-60/ADR cells treated with DAC at concentrations of 0.5 and 1.0 µmol/l sequentially combined with ACLA was significantly higher compared with that with ACLA alone (P<0.001 for both). DNMT1 expression was significantly repressed following treatment with 1.0 µmol/l DAC. Of the 11 patients, 8 (72.7%) received induction therapy with DAC sequentially combined with CAG agents and achieved complete remission (CR) after 2 cycles of treatment; however, 3 (27.3%) patients did not achieve remission. Myelosuppression was observed in all 11 patients and pulmonary infections developed in 9 patients (81.8%) during the course of the study. At the last follow-up, 7 of the 8 patients who achieved CR remained in remission. The median follow-up was 6 months (range, 3-18 months). Therefore, pretreatment with DAC may increase the sensitivity of HL-60/ADR cells to ACLA via the epigenetic modulation of demethylation and the sequential administration of DAC and CAG regimen appears to be safe and effective for the treatment of patients with high-risk AML.

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Section: Discussionsupporting

confidence: 92%

Palliative chemotherapy followed by methylation inhibitor in high-risk acute myeloid leukemia: An in vitro and clinical study

Ding

Wang

Jiang

et al. 2015

Molecular and Clinical Oncology

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“…Unlike other chemotherapy resistance mechanisms, DNA methylation is reversible by demethylating drugs; decitabine is one of the most potent demethylating drugs. Decitabine has been used in clinical trials for hematological and solid malignancies, with the major side effect being transient and manageable myelosuppression [12]–[15]. We showed from previous studies in a preclinical HNSCC model that decitabine not only inhibits tumor growth, it also treats pain-induced loss of function [16].…”

Section: Introductionmentioning

confidence: 97%

Decitabine Rescues Cisplatin Resistance in Head and Neck Squamous Cell Carcinoma

et al. 2014

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Cisplatin resistance in head and neck squamous cell carcinoma (HNSCC) reduces survival. In this study we hypothesized that methylation of key genes mediates cisplatin resistance. We determined whether a demethylating drug, decitabine, could augment the anti-proliferative and apoptotic effects of cisplatin on SCC-25/CP, a cisplatin-resistant tongue SCC cell line. We showed that decitabine treatment restored cisplatin sensitivity in SCC-25/CP and significantly reduced the cisplatin dose required to induce apoptosis. We then created a xenograft model with SCC-25/CP and determined that decitabine and cisplatin combination treatment resulted in significantly reduced tumor growth and mechanical allodynia compared to control. To establish a gene classifier we quantified methylation in cancer tissue of cisplatin-sensitive and cisplatin-resistant HNSCC patients. Cisplatin-sensitive and cisplatin-resistant patient tumors had distinct methylation profiles. When we quantified methylation and expression of genes in the classifier in HNSCC cells in vitro, we showed that decitabine treatment of cisplatin-resistant HNSCC cells reversed methylation and gene expression toward a cisplatin-sensitive profile. The study provides direct evidence that decitabine restores cisplatin sensitivity in in vitro and in vivo models of HNSCC. Combination treatment of cisplatin and decitabine significantly reduces HNSCC growth and HNSCC pain. Furthermore, gene methylation could be used as a biomarker of cisplatin-resistance.

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“…1), a DAN methyltransferase inhibitor, possesses anti-cancer activities by inhibiting of DAN methylation, leading to DNA hypomethylation and resulting in gene re-expression and cellular differentiation [1][2][3]. It has been widely used in clinic for the treatment of myelodysplastic syndrome, acute myeloid leukemia and chronic myeloid leukemia [4]. In the last 10 years, it was proposed to combine DNA methyltransferase inhibitors with other agents for the treatment of patients with refractory solid tumor malignancies [4,5].…”

Section: Introductionmentioning

confidence: 99%

Development and validation of a liquid chromatography–tandem mass spectrometry method for quantification of decitabine in rat plasma

Xu¹,

lv²,

Qiao³

et al. 2012

Journal of Chromatography B

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Decitabine

Cited by 39 publications

References 133 publications

Palliative chemotherapy followed by methylation inhibitor in high-risk acute myeloid leukemia: An in vitro and clinical study

Palliative chemotherapy followed by methylation inhibitor in high-risk acute myeloid leukemia: An in vitro and clinical study

Decitabine Rescues Cisplatin Resistance in Head and Neck Squamous Cell Carcinoma

Development and validation of a liquid chromatography–tandem mass spectrometry method for quantification of decitabine in rat plasma

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