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Richard L. Momparler - One of the best experts on this subject based on the ideXlab platform.

  • pharmacology of 5 aza 2 Deoxycytidine decitabine
    Seminars in Hematology, 2005
    Co-Authors: Richard L. Momparler
    Abstract:

    The preclinical pharmacology of 5-aza-2′-Deoxycytidine (decitabine, 5AZA-CdR) is reviewed. 5AZA-CdR, an analogue of Deoxycytidine, is a prodrug that requires metabolic activation by Deoxycytidine kinase. The active inhibitor in the cell is its triphosphate form (5AZA-dCTP), which incorporates very readily into DNA to produce an inhibition of DNA methyltransferase. The mechanism responsible for the antileukemic action of 5AZA-CdR is related to its reversal of epigenetic silencing by aberrant DNA methylation of genes that suppress leukemiogenesis. 5AZA-CdR is an S-phase-specific agent. At concentrations in the range of micromolars this analogue can induce terminal differentiation and loss of clonogenicity of human leukemic cells. Drug resistance to 5AZA-CdR occurs primarily by reduction in Deoxycytidine kinase activity or increase in the activity of cytidine deaminase, the enzyme that inactivates this analogue. 5AZA-CdR is a very potent antileukemic agent in animal models, more effective than the related antileukemic drug, cytosine arabinoside. In humans, 5AZA-CdR has a short half-life of 15 to 25 minutes due to rapid inactivation by liver cytidine deaminase. The major toxicity produced by 5AZA-CdR is myelosuppression. Preliminary clinical studies in patients with hematologic malignancies indicate that 5AZA-CdR is an active chemotherapeutic agent. The optimal dose-schedule for this interesting epigenetic agent with a novel mechanism of action remains to be determined. Translation of the pharmacology of 5AZA-CdR into therapeutic regimens based on scientific rationale can be used to obtain this objective.

  • synergistic antineoplastic action of dna methylation inhibitor 5 aza 2 Deoxycytidine and histone deacetylase inhibitor depsipeptide on human breast carcinoma cells
    International Journal of Cancer, 2003
    Co-Authors: Melanie Primeau, Jacynthe Gagnon, Richard L. Momparler
    Abstract:

    During tumorigenesis, cancer-related genes can be silenced by aberrant DNA methylation and by changes in chromatin structure. It has been reported that 5-aza-2′-Deoxycytidine, a potent inhibitor of DNA methylation, in combination with histone deacetylase inhibitors, can produce a synergistic reactivation of these genes. The aim of our study was to investigate the in vitro antineoplastic activity of 5-aza-2′-Deoxycytidine in combination with depsipeptide, a potent histone deacetylase inhibitor, against MDA-MB-231 and MDA-MB-435 human breast carcinoma cell lines. We observed that the combination of 5-aza-2′-Deoxycytidine and depsipeptide produced a synergistic antineoplastic effect against these tumor cells as compared to either agent administered alone. We also investigated the effect of this drug combination on the activation of maspin and gelsolin expression. These 2 genes whose function is to suppress tumor metastasis have been reported to be silenced by epigenetic events in breast cancer. Using semi-quantitative RT-PCR, we observed that 5-aza-2′-Deoxycytidine in combination with depsipeptide produced a greater reactivation of both maspin and gelsolin as compared to each agent alone. The synergistic interaction between 5-aza-2′-Deoxycytidine and depsipeptide on breast carcinoma cell lines provides a rationale to investigate this interesting drug combination in future clinical trials on patients with advanced breast cancer. © 2002 Wiley-Liss, Inc.

  • synergistic antineoplastic action of dna methylation inhibitor 5 aza 2 Deoxycytidine and histone deacetylase inhibitor depsipeptide on human breast carcinoma cells
    International Journal of Cancer, 2003
    Co-Authors: Melanie Primeau, Jacynthe Gagnon, Richard L. Momparler
    Abstract:

    During tumorigenesis, cancer-related genes can be silenced by aberrant DNA methylation and by changes in chromatin structure. It has been reported that 5-aza-2'-Deoxycytidine, a potent inhibitor of DNA methylation, in combination with histone deacetylase inhibitors, can produce a synergistic reactivation of these genes. The aim of our study was to investigate the in vitro antineoplastic activity of 5-aza-2'-Deoxycytidine in combination with depsipeptide, a potent histone deacetylase inhibitor, against MDA-MB-231 and MDA-MB-435 human breast carcinoma cell lines. We observed that the combination of 5-aza-2'-Deoxycytidine and depsipeptide produced a synergistic antineoplastic effect against these tumor cells as compared to either agent administered alone. We also investigated the effect of this drug combination on the activation of maspin and gelsolin expression. These 2 genes whose function is to suppress tumor metastasis have been reported to be silenced by epigenetic events in breast cancer. Using semi-quantitative RT-PCR, we observed that 5-aza-2'-Deoxycytidine in combination with depsipeptide produced a greater reactivation of both maspin and gelsolin as compared to each agent alone. The synergistic interaction between 5-aza-2'-Deoxycytidine and depsipeptide on breast carcinoma cell lines provides a rationale to investigate this interesting drug combination in future clinical trials on patients with advanced breast cancer.

Ryszard Olinski - One of the best experts on this subject based on the ideXlab platform.

  • quantification of dna modifications using two dimensional ultraperformance liquid chromatography tandem mass spectrometry 2d uplc ms ms
    Methods of Molecular Biology, 2021
    Co-Authors: Marta Starczak, Ryszard Olinski, Maciej Gawronski, Daniel Gackowski
    Abstract:

    Our hereby presented methodology is suitable for reliable assessment of the most common DNA modifications which arise as a product of fundamental metabolic processes. 8-oxoguanine, one of the oxidatively modified DNA bases is a typical biomarker of oxidative stress. A noncanonical base, uracil, may also be present in small quantities in DNA. Ten-eleven translocation (TET) proteins are involved in oxidation of 5-methylcytosine to 5-hydroxymethylcytosine which can be further oxidized to 5-formylcytosine and 5-carboxycytosine. 5-hydroxymethyluracil may be formed in deamination reaction of 5-hydroxymethylcytosine or can also be generated by TET enzymes. All the above mentioned modifications seem to play some regulatory roles. Here, we provide a protocol for isotope-dilution automated online two-dimensional ultraperformance liquid chromatography with tandem mass spectrometry (2D-UPLC-MS/MS) for direct measurement of 5-methyl-2'-Deoxycytidine, 5-(hydroxymethyl)-2'-Deoxycytidine, 5-formyl-2'-Deoxycytidine, 5-carboxy-2'-Deoxycytidine, 5-(hydroxymethyl)-2'-deoxyuridine, 2'-deoxyuridine, and 8-oxo-2'-deoxyguanosine. We also provide optimized protocols for extraction of DNA, fully compatible with the downstream MS/MS analysis.

  • accurate direct and high throughput analyses of a broad spectrum of endogenously generated dna base modifications with isotope dilution two dimensional ultraperformance liquid chromatography with tandem mass spectrometry possible clinical implication
    Analytical Chemistry, 2016
    Co-Authors: Daniel Gackowski, Marta Starczak, Martyna Modrzejewska, Ewelina Zarakowska, Anna Szpila, Zbigniew Banaszkiewicz, Ryszard Olinski
    Abstract:

    Our hereby presented methodology is suitable for reliable assessment of the most common unavoidable DNA modifications which arise as a product of fundamental metabolic processes. 8-Oxoguanine, one of the oxidatively modified DNA bases, is a typical biomarker of oxidative stress. A noncanonical base, uracil, may be also present in small quantities in DNA. A set of ten-eleven translocation (TET) proteins are involved in oxidation of 5-methylcytosine to 5-hydroxymethylcytosine which can be further oxidized to 5-formylcytosine and 5-carboxycytosine. 5-Hydroxymethyluracil may be formed in deamination reaction of 5-hydroxymethylcytosine or can be also generated by TET enzymes. All of the aforementioned modifications seem to play some regulatory roles. We applied isotope-dilution automated online two-dimensional ultraperformance liquid chromatography with tandem mass spectrometry (2D-UPLC-MS/MS) for direct measurement of the 5-methyl-2′-Deoxycytidine, 5-(hydroxymethyl)-2′-Deoxycytidine, 5-formyl-2′-Deoxycytidine...

  • tissue specific differences in dna modifications 5 hydroxymethylcytosine 5 formylcytosine 5 carboxylcytosine and 5 hydroxymethyluracil and their interrelationships
    PLOS ONE, 2015
    Co-Authors: Daniel Gackowski, Marta Starczak, Martyna Modrzejewska, Ewelina Zarakowska, Ryszard Olinski
    Abstract:

    Background Replication-independent active/enzymatic demethylation may be an important process in the functioning of somatic cells. The most plausible mechanisms of active 5-methylcytosine demethylation, leading to activation of previously silenced genes, involve ten-eleven translocation (TET) proteins that participate in oxidation of 5-methylcytosine to 5-hydroxymethylcytosine which can be further oxidized to 5-formylcytosine and 5-carboxylcytosine. Recently, 5-hydroxymethylcytosine was demonstrated to be a relatively stable modification, and the previously observed substantial differences in the level of this modification in various murine tissues were shown to depend mostly on cell proliferation rate. Some experimental evidence supports the hypothesis that 5-hydroxymethyluracil may be also generated by TET enzymes and has epigenetic functions. Results Using an isotope-dilution automated online two-dimensional ultra-performance liquid chromatography with tandem mass spectrometry, we have analyzed, for the first time, all the products of active DNA demethylation pathway: 5-methyl-2′-Deoxycytidine, 5-hydroxymethyl-2′-Deoxycytidine, 5-formyl-2′-Deoxycytidine and 5-carboxyl-2′-Deoxycytidine, as well as 5-hydroxymethyl-2′-deoxyuridine, in DNA isolated from various rat and porcine tissues. A strong significant inverse linear correlation was found between the proliferation rate of cells and the global level of 5-hydroxymethyl-2′-Deoxycytidine in both porcine (R2 = 0.88) and rat tissues (R2 = 0.83); no such relationship was observed for 5-formyl-2′-Deoxycytidine and 5-carboxyl-2′-Deoxycytidine. Moreover, a substrate-product correlation was demonstrated for the two consecutive steps of iterative oxidation pathway: between 5-hydroxymethyl-2′-Deoxycytidine and its product 5-formyl-2′-Deoxycytidine, as well as between 5-formyl-2′-Deoxycytidine and 5-carboxyl-2′-Deoxycytidine (R2 = 0.60 and R2 = 0.71, respectively). Conclusions Good correlations within the substrate-product sets of iterative oxidation pathway may suggest that a part of 5-formyl-2′-Deoxycytidine and/or 5-carboxyl-2′-Deoxycytidine can be directly linked to a small portion of 5-hydroxymethyl-2′-Deoxycytidine which defines the active demethylation process.

  • comparison of the absolute level of epigenetic marks 5 methylcytosine 5 hydroxymethylcytosine and 5 hydroxymethyluracil between human leukocytes and sperm
    Biology of Reproduction, 2014
    Co-Authors: Daniel Gackowski, Marek Foksinski, Rafal Rozalski, Ryszard Olinski
    Abstract:

    ABSTRACT 5-Methylcytosine is one of the most important epigenetic modifications and has a profound impact on embryonic development. After gamete fusion, there is a widespread and rapid active demethylation process of sperm DNA, which suggests that the paternal epigenome has an important role during embryonic development. To better understand the epigenome of sperm DNA and its possible involvement in a developing embryo, we determined epigenetic marks in human sperm DNA and in surrogate somatic tissue leukocytes; the analyzed epigenetic modifications included 5-methyl-2′-Deoxycytidine, 5-hydroxymethyl-2′-Deoxycytidine, and 5-hydroxymethyl-2′-deoxyuridine. For absolute determination of the modification, we used liquid chromatography with UV detection and tandem mass spectrometry techniques with isotopically labeled internal standards. Our analyses demonstrated, for the first time to date, that absolute global values of 5-methyl-2′-Deoxycytidine, 5-hydroxymethyl-2′-Deoxycytidine, and 5-hydroxymethyl-2′-deoxy...

  • comparison of the absolute level of epigenetic marks 5 methylcytosine 5 hydroxymethylcytosine and 5 hydroxymethyluracil between human leukocytes and sperm
    Biology of Reproduction, 2014
    Co-Authors: Jolanta Guz, Marek Foksinski, Daniel Gackowski, Rafal Rozalski, Ryszard Olinski
    Abstract:

    5-Methylcytosine is one of the most important epigenetic modifications and has a profound impact on embryonic development. After gamete fusion, there is a widespread and rapid active demethylation process of sperm DNA, which suggests that the paternal epigenome has an important role during embryonic development. To better understand the epigenome of sperm DNA and its possible involvement in a developing embryo, we determined epigenetic marks in human sperm DNA and in surrogate somatic tissue leukocytes; the analyzed epigenetic modifications included 5-methyl-2'-Deoxycytidine, 5-hydroxymethyl-2'-Deoxycytidine, and 5-hydroxymethyl-2'-deoxyuridine. For absolute determination of the modification, we used liquid chromatography with UV detection and tandem mass spectrometry techniques with isotopically labeled internal standards. Our analyses demonstrated, for the first time to date, that absolute global values of 5-methyl-2'-Deoxycytidine, 5-hydroxymethyl-2'-Deoxycytidine, and 5-hydroxymethyl-2'-deoxyuridine in sperm are highly statistically different from those observed for leukocyte DNA, with respective mean values of 3.815% versus 4.307%, 0.797 versus 2.945 per 10⁴ deoxynucleosides, and 5.209 versus 0.492 per 10⁶ deoxynucleosides. We hypothesize that an exceptionally high value of 5-hydroxymethyluracil in sperm (>10-fold higher than in leukocytes) may play a not yet recognized regulatory role in the paternal genome.

Daniel Gackowski - One of the best experts on this subject based on the ideXlab platform.

  • quantification of dna modifications using two dimensional ultraperformance liquid chromatography tandem mass spectrometry 2d uplc ms ms
    Methods of Molecular Biology, 2021
    Co-Authors: Marta Starczak, Ryszard Olinski, Maciej Gawronski, Daniel Gackowski
    Abstract:

    Our hereby presented methodology is suitable for reliable assessment of the most common DNA modifications which arise as a product of fundamental metabolic processes. 8-oxoguanine, one of the oxidatively modified DNA bases is a typical biomarker of oxidative stress. A noncanonical base, uracil, may also be present in small quantities in DNA. Ten-eleven translocation (TET) proteins are involved in oxidation of 5-methylcytosine to 5-hydroxymethylcytosine which can be further oxidized to 5-formylcytosine and 5-carboxycytosine. 5-hydroxymethyluracil may be formed in deamination reaction of 5-hydroxymethylcytosine or can also be generated by TET enzymes. All the above mentioned modifications seem to play some regulatory roles. Here, we provide a protocol for isotope-dilution automated online two-dimensional ultraperformance liquid chromatography with tandem mass spectrometry (2D-UPLC-MS/MS) for direct measurement of 5-methyl-2'-Deoxycytidine, 5-(hydroxymethyl)-2'-Deoxycytidine, 5-formyl-2'-Deoxycytidine, 5-carboxy-2'-Deoxycytidine, 5-(hydroxymethyl)-2'-deoxyuridine, 2'-deoxyuridine, and 8-oxo-2'-deoxyguanosine. We also provide optimized protocols for extraction of DNA, fully compatible with the downstream MS/MS analysis.

  • accurate direct and high throughput analyses of a broad spectrum of endogenously generated dna base modifications with isotope dilution two dimensional ultraperformance liquid chromatography with tandem mass spectrometry possible clinical implication
    Analytical Chemistry, 2016
    Co-Authors: Daniel Gackowski, Marta Starczak, Martyna Modrzejewska, Ewelina Zarakowska, Anna Szpila, Zbigniew Banaszkiewicz, Ryszard Olinski
    Abstract:

    Our hereby presented methodology is suitable for reliable assessment of the most common unavoidable DNA modifications which arise as a product of fundamental metabolic processes. 8-Oxoguanine, one of the oxidatively modified DNA bases, is a typical biomarker of oxidative stress. A noncanonical base, uracil, may be also present in small quantities in DNA. A set of ten-eleven translocation (TET) proteins are involved in oxidation of 5-methylcytosine to 5-hydroxymethylcytosine which can be further oxidized to 5-formylcytosine and 5-carboxycytosine. 5-Hydroxymethyluracil may be formed in deamination reaction of 5-hydroxymethylcytosine or can be also generated by TET enzymes. All of the aforementioned modifications seem to play some regulatory roles. We applied isotope-dilution automated online two-dimensional ultraperformance liquid chromatography with tandem mass spectrometry (2D-UPLC-MS/MS) for direct measurement of the 5-methyl-2′-Deoxycytidine, 5-(hydroxymethyl)-2′-Deoxycytidine, 5-formyl-2′-Deoxycytidine...

  • tissue specific differences in dna modifications 5 hydroxymethylcytosine 5 formylcytosine 5 carboxylcytosine and 5 hydroxymethyluracil and their interrelationships
    PLOS ONE, 2015
    Co-Authors: Daniel Gackowski, Marta Starczak, Martyna Modrzejewska, Ewelina Zarakowska, Ryszard Olinski
    Abstract:

    Background Replication-independent active/enzymatic demethylation may be an important process in the functioning of somatic cells. The most plausible mechanisms of active 5-methylcytosine demethylation, leading to activation of previously silenced genes, involve ten-eleven translocation (TET) proteins that participate in oxidation of 5-methylcytosine to 5-hydroxymethylcytosine which can be further oxidized to 5-formylcytosine and 5-carboxylcytosine. Recently, 5-hydroxymethylcytosine was demonstrated to be a relatively stable modification, and the previously observed substantial differences in the level of this modification in various murine tissues were shown to depend mostly on cell proliferation rate. Some experimental evidence supports the hypothesis that 5-hydroxymethyluracil may be also generated by TET enzymes and has epigenetic functions. Results Using an isotope-dilution automated online two-dimensional ultra-performance liquid chromatography with tandem mass spectrometry, we have analyzed, for the first time, all the products of active DNA demethylation pathway: 5-methyl-2′-Deoxycytidine, 5-hydroxymethyl-2′-Deoxycytidine, 5-formyl-2′-Deoxycytidine and 5-carboxyl-2′-Deoxycytidine, as well as 5-hydroxymethyl-2′-deoxyuridine, in DNA isolated from various rat and porcine tissues. A strong significant inverse linear correlation was found between the proliferation rate of cells and the global level of 5-hydroxymethyl-2′-Deoxycytidine in both porcine (R2 = 0.88) and rat tissues (R2 = 0.83); no such relationship was observed for 5-formyl-2′-Deoxycytidine and 5-carboxyl-2′-Deoxycytidine. Moreover, a substrate-product correlation was demonstrated for the two consecutive steps of iterative oxidation pathway: between 5-hydroxymethyl-2′-Deoxycytidine and its product 5-formyl-2′-Deoxycytidine, as well as between 5-formyl-2′-Deoxycytidine and 5-carboxyl-2′-Deoxycytidine (R2 = 0.60 and R2 = 0.71, respectively). Conclusions Good correlations within the substrate-product sets of iterative oxidation pathway may suggest that a part of 5-formyl-2′-Deoxycytidine and/or 5-carboxyl-2′-Deoxycytidine can be directly linked to a small portion of 5-hydroxymethyl-2′-Deoxycytidine which defines the active demethylation process.

  • comparison of the absolute level of epigenetic marks 5 methylcytosine 5 hydroxymethylcytosine and 5 hydroxymethyluracil between human leukocytes and sperm
    Biology of Reproduction, 2014
    Co-Authors: Daniel Gackowski, Marek Foksinski, Rafal Rozalski, Ryszard Olinski
    Abstract:

    ABSTRACT 5-Methylcytosine is one of the most important epigenetic modifications and has a profound impact on embryonic development. After gamete fusion, there is a widespread and rapid active demethylation process of sperm DNA, which suggests that the paternal epigenome has an important role during embryonic development. To better understand the epigenome of sperm DNA and its possible involvement in a developing embryo, we determined epigenetic marks in human sperm DNA and in surrogate somatic tissue leukocytes; the analyzed epigenetic modifications included 5-methyl-2′-Deoxycytidine, 5-hydroxymethyl-2′-Deoxycytidine, and 5-hydroxymethyl-2′-deoxyuridine. For absolute determination of the modification, we used liquid chromatography with UV detection and tandem mass spectrometry techniques with isotopically labeled internal standards. Our analyses demonstrated, for the first time to date, that absolute global values of 5-methyl-2′-Deoxycytidine, 5-hydroxymethyl-2′-Deoxycytidine, and 5-hydroxymethyl-2′-deoxy...

  • comparison of the absolute level of epigenetic marks 5 methylcytosine 5 hydroxymethylcytosine and 5 hydroxymethyluracil between human leukocytes and sperm
    Biology of Reproduction, 2014
    Co-Authors: Jolanta Guz, Marek Foksinski, Daniel Gackowski, Rafal Rozalski, Ryszard Olinski
    Abstract:

    5-Methylcytosine is one of the most important epigenetic modifications and has a profound impact on embryonic development. After gamete fusion, there is a widespread and rapid active demethylation process of sperm DNA, which suggests that the paternal epigenome has an important role during embryonic development. To better understand the epigenome of sperm DNA and its possible involvement in a developing embryo, we determined epigenetic marks in human sperm DNA and in surrogate somatic tissue leukocytes; the analyzed epigenetic modifications included 5-methyl-2'-Deoxycytidine, 5-hydroxymethyl-2'-Deoxycytidine, and 5-hydroxymethyl-2'-deoxyuridine. For absolute determination of the modification, we used liquid chromatography with UV detection and tandem mass spectrometry techniques with isotopically labeled internal standards. Our analyses demonstrated, for the first time to date, that absolute global values of 5-methyl-2'-Deoxycytidine, 5-hydroxymethyl-2'-Deoxycytidine, and 5-hydroxymethyl-2'-deoxyuridine in sperm are highly statistically different from those observed for leukocyte DNA, with respective mean values of 3.815% versus 4.307%, 0.797 versus 2.945 per 10⁴ deoxynucleosides, and 5.209 versus 0.492 per 10⁶ deoxynucleosides. We hypothesize that an exceptionally high value of 5-hydroxymethyluracil in sperm (>10-fold higher than in leukocytes) may play a not yet recognized regulatory role in the paternal genome.

Melanie Primeau - One of the best experts on this subject based on the ideXlab platform.

  • synergistic antineoplastic action of dna methylation inhibitor 5 aza 2 Deoxycytidine and histone deacetylase inhibitor depsipeptide on human breast carcinoma cells
    International Journal of Cancer, 2003
    Co-Authors: Melanie Primeau, Jacynthe Gagnon, Richard L. Momparler
    Abstract:

    During tumorigenesis, cancer-related genes can be silenced by aberrant DNA methylation and by changes in chromatin structure. It has been reported that 5-aza-2′-Deoxycytidine, a potent inhibitor of DNA methylation, in combination with histone deacetylase inhibitors, can produce a synergistic reactivation of these genes. The aim of our study was to investigate the in vitro antineoplastic activity of 5-aza-2′-Deoxycytidine in combination with depsipeptide, a potent histone deacetylase inhibitor, against MDA-MB-231 and MDA-MB-435 human breast carcinoma cell lines. We observed that the combination of 5-aza-2′-Deoxycytidine and depsipeptide produced a synergistic antineoplastic effect against these tumor cells as compared to either agent administered alone. We also investigated the effect of this drug combination on the activation of maspin and gelsolin expression. These 2 genes whose function is to suppress tumor metastasis have been reported to be silenced by epigenetic events in breast cancer. Using semi-quantitative RT-PCR, we observed that 5-aza-2′-Deoxycytidine in combination with depsipeptide produced a greater reactivation of both maspin and gelsolin as compared to each agent alone. The synergistic interaction between 5-aza-2′-Deoxycytidine and depsipeptide on breast carcinoma cell lines provides a rationale to investigate this interesting drug combination in future clinical trials on patients with advanced breast cancer. © 2002 Wiley-Liss, Inc.

  • synergistic antineoplastic action of dna methylation inhibitor 5 aza 2 Deoxycytidine and histone deacetylase inhibitor depsipeptide on human breast carcinoma cells
    International Journal of Cancer, 2003
    Co-Authors: Melanie Primeau, Jacynthe Gagnon, Richard L. Momparler
    Abstract:

    During tumorigenesis, cancer-related genes can be silenced by aberrant DNA methylation and by changes in chromatin structure. It has been reported that 5-aza-2'-Deoxycytidine, a potent inhibitor of DNA methylation, in combination with histone deacetylase inhibitors, can produce a synergistic reactivation of these genes. The aim of our study was to investigate the in vitro antineoplastic activity of 5-aza-2'-Deoxycytidine in combination with depsipeptide, a potent histone deacetylase inhibitor, against MDA-MB-231 and MDA-MB-435 human breast carcinoma cell lines. We observed that the combination of 5-aza-2'-Deoxycytidine and depsipeptide produced a synergistic antineoplastic effect against these tumor cells as compared to either agent administered alone. We also investigated the effect of this drug combination on the activation of maspin and gelsolin expression. These 2 genes whose function is to suppress tumor metastasis have been reported to be silenced by epigenetic events in breast cancer. Using semi-quantitative RT-PCR, we observed that 5-aza-2'-Deoxycytidine in combination with depsipeptide produced a greater reactivation of both maspin and gelsolin as compared to each agent alone. The synergistic interaction between 5-aza-2'-Deoxycytidine and depsipeptide on breast carcinoma cell lines provides a rationale to investigate this interesting drug combination in future clinical trials on patients with advanced breast cancer.

Jacynthe Gagnon - One of the best experts on this subject based on the ideXlab platform.

  • synergistic antineoplastic action of dna methylation inhibitor 5 aza 2 Deoxycytidine and histone deacetylase inhibitor depsipeptide on human breast carcinoma cells
    International Journal of Cancer, 2003
    Co-Authors: Melanie Primeau, Jacynthe Gagnon, Richard L. Momparler
    Abstract:

    During tumorigenesis, cancer-related genes can be silenced by aberrant DNA methylation and by changes in chromatin structure. It has been reported that 5-aza-2′-Deoxycytidine, a potent inhibitor of DNA methylation, in combination with histone deacetylase inhibitors, can produce a synergistic reactivation of these genes. The aim of our study was to investigate the in vitro antineoplastic activity of 5-aza-2′-Deoxycytidine in combination with depsipeptide, a potent histone deacetylase inhibitor, against MDA-MB-231 and MDA-MB-435 human breast carcinoma cell lines. We observed that the combination of 5-aza-2′-Deoxycytidine and depsipeptide produced a synergistic antineoplastic effect against these tumor cells as compared to either agent administered alone. We also investigated the effect of this drug combination on the activation of maspin and gelsolin expression. These 2 genes whose function is to suppress tumor metastasis have been reported to be silenced by epigenetic events in breast cancer. Using semi-quantitative RT-PCR, we observed that 5-aza-2′-Deoxycytidine in combination with depsipeptide produced a greater reactivation of both maspin and gelsolin as compared to each agent alone. The synergistic interaction between 5-aza-2′-Deoxycytidine and depsipeptide on breast carcinoma cell lines provides a rationale to investigate this interesting drug combination in future clinical trials on patients with advanced breast cancer. © 2002 Wiley-Liss, Inc.

  • synergistic antineoplastic action of dna methylation inhibitor 5 aza 2 Deoxycytidine and histone deacetylase inhibitor depsipeptide on human breast carcinoma cells
    International Journal of Cancer, 2003
    Co-Authors: Melanie Primeau, Jacynthe Gagnon, Richard L. Momparler
    Abstract:

    During tumorigenesis, cancer-related genes can be silenced by aberrant DNA methylation and by changes in chromatin structure. It has been reported that 5-aza-2'-Deoxycytidine, a potent inhibitor of DNA methylation, in combination with histone deacetylase inhibitors, can produce a synergistic reactivation of these genes. The aim of our study was to investigate the in vitro antineoplastic activity of 5-aza-2'-Deoxycytidine in combination with depsipeptide, a potent histone deacetylase inhibitor, against MDA-MB-231 and MDA-MB-435 human breast carcinoma cell lines. We observed that the combination of 5-aza-2'-Deoxycytidine and depsipeptide produced a synergistic antineoplastic effect against these tumor cells as compared to either agent administered alone. We also investigated the effect of this drug combination on the activation of maspin and gelsolin expression. These 2 genes whose function is to suppress tumor metastasis have been reported to be silenced by epigenetic events in breast cancer. Using semi-quantitative RT-PCR, we observed that 5-aza-2'-Deoxycytidine in combination with depsipeptide produced a greater reactivation of both maspin and gelsolin as compared to each agent alone. The synergistic interaction between 5-aza-2'-Deoxycytidine and depsipeptide on breast carcinoma cell lines provides a rationale to investigate this interesting drug combination in future clinical trials on patients with advanced breast cancer.