The Experts below are selected from a list of 174 Experts worldwide ranked by ideXlab platform
Jill Bargonetti - One of the best experts on this subject based on the ideXlab platform.
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DNA Adducts of Decarbamoyl Mitomycin C Efficiently Kill Cells without Wild-Type p53 Resulting from Proteasome-Mediated Degradation of Checkpoint Protein 1
Chemical research in toxicology, 2010Co-Authors: Ernest K. Boamah, Angelika Brekman, Maria Tomasz, Natura Myeku, Maria E. Figueiredo-pereira, Senyene E. Hunter, Joel N. Meyer, R. Bhosle, Jill BargonettiAbstract:The Mitomycin Derivative 10-decarbamoyl Mitomycin C (DMC) more rapidly activates a p53-independent cell death pathway than Mitomycin C (MC). We recently documented that an increased proportion of mitosene1-β-adduct formation occurs in human cells treated with DMC in comparison to those treated with MC. Here, we compare the cellular and molecular response of human cancer cells treated with MC and DMC. We find the increase in mitosene 1-β-adduct formation correlates with a condensed nuclear morphology and increased cytotoxicity in human cancer cells with or without p53. DMC caused more DNA damage than MC in the nuclear and mitochondrial genomes. Checkpoint 1 protein (Chk1) was depleted following DMC, and the depletion of Chk1 by DMC was achieved through the ubiquitin proteasome pathway since chemical inhibition of the proteasome protected against Chk1 depletion. Gene silencing of Chk1 by siRNA increased the cytotoxicity of MC. DMC treatment caused a decrease in the level of total ubiquitinated proteins with...
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Abstract #5366: The N2-deoxyguanosine adducts of Mitomycins with mitosene-1-\#914; stereochemistry efficiently kill cells with compromised p53 through proteasome-mediated degradation of Chk1
Cancer Research, 2009Co-Authors: Ernest K. Boamah, Angelika Brekman, Maria Tomasz, Natura Myeku, Maria Figueredo-pereira, Jill BargonettiAbstract:Despite the importance of p53-independent cell death, little is known about the activation of such pathways. At least 50 percent of all cancers do not have a functional p53-pathway. We see that the Mitomycin Derivative 10-decarbamoyl Mitomycin C (DMC), in contrast to Mitomycin C (MC), can rapidly activate a p53-independent cell death pathway, which lacks markers for activation of an apoptotic death pathway. We recently reported that MC and DMC induce cellular cytotoxicity in human cells with wild-type p53, while only DMC shows significant cell death activity in the absence of wild-type p53. Nevertheless, it was unclear if the difference in cell death activity was due to the observed ability of DMC to form the alternative stereoisomeric 1-\#946; mono and 1-\#946; cross-link DNA adducts of guanine in human cell lines resulting in differential molecular signaling. In this study, we compared the DNA adducts and the cellular regulation of molecular targets upon treatment with MC and DMC in human cancer cell lines with or without wild-type p53. Compared to MC, DMC treatment produced substantially more 1-\#946; mono- and 1-\#946; cross-link DNA adducts, as measured by liquid chromatography/electrospray tandem mass spectrometry (Paz et al. Chem. Res.Toxicol., In Press). In addition, DMC-treatment resulted in abnormal nuclear morphology and increased cytotoxicity in human cancer cells with compromised p53 activity. We further established that DMC provoked a p53-independent cell death pathway that correlates with the formation of novel stereoisomeric DNA-adducts leading to down-regulation of Chk-1. Interestingly, Chk1 depletion was prevented by inhibition of the ubiquitin proteasome pathway, suggesting that DMC-DNA adducts may activate this proteolytic pathway. However, the observed decrease in the levels of ubiquitinated proteins upon DMC treatment was not caused by a direct change in proteasome activity suggesting that changed kinase signaling might be the cause of an activated pathway. Both MC and DMC have similar cytotoxicity upon depletion of Chk1 by siRNA, implicating loss of Chk1 as an important component in the DNA damage induced cell death pathway. In summary, we demonstrated that DMC generates significantly more mitosene-1-\#946; stereoisomeric DNA adducts than MC and causes down-regulation of Chk1 through the ubiquitin proteasome pathway. These studies suggest that mitosene-1-\#946; guanine adducts of DNA induce rapid and effective cell death of cancers with compromised p53, a cell type not rapidly killed by MC. This work was supported by a NIH SCORE Grant (1SC1CA137843-01), The Breast Cancer Research Foundation and was facilitated by a NIH Research Centers in Minority Institutions award from the Division of Research Resources (RR-03037) to Hunter College. EB is supported by the MBRS-RISE minority program at Hunter College. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5366.
Ernst A. De Bruijn - One of the best experts on this subject based on the ideXlab platform.
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Intravesical Drug Delivery
Clinical Pharmacokinetics, 1999Co-Authors: Martin Highley, Robert A. A. Maes, Allan T. Oosterom, Ernst A. De BruijnAbstract:Intravesical drug administration is widely used in the treatment of patients with superficial bladder cancer, and aims to optimise drug delivery in the vicinity of the tumour and reduce systemic availability. The most commonly employed intravesical agents in patients with superficial bladder cancer are Mitomycin (Mitomycin C), thiotepa, etoglucid (ethoglucid), anthracyclines such as doxorubicin, bacille Calmette-Guérin (BCG) and, more recently, taxol and the new Mitomycin Derivative KW-2149. Recurrence rates in patients with superficial bladder cancer have been substantially reduced by combined transurethral resection and intravesical pharmacotherapy. The high concentration of cytotoxics in urine and tumour tissue explain the high efficacy rates. Furthermore, the low systemic availability of most intravesical agents is consistent with the low frequency of acute and delayed systemic adverse effects. Systemic toxicity is almost negligible, except in the case of thiotepa, and local toxicity is transient and tolerable. Pharmacokinetic models of drug absorption from the bladder have been developed, both in animals and humans. These have led to the identification of optimal intravescial treatment regimens.
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Intravesical drug delivery. Pharmacokinetic and clinical considerations.
Clinical pharmacokinetics, 1999Co-Authors: Martin Highley, Allan T. Van Oosterom, Robert A. A. Maes, Ernst A. De BruijnAbstract:Intravesical drug administration is widely used in the treatment of patients with superficial bladder cancer, and aims to optimise drug delivery in the vicinity of the tumour and reduce systemic availability. The most commonly employed intravesical agents in patients with superficial bladder cancer are Mitomycin (Mitomycin C), thiotepa, etoglucid (ethoglucid), anthracyclines such as doxorubicin, bacille Calmette-Guerin (BCG) and, more recently, taxol and the new Mitomycin Derivative KW-2149.
Ernest K. Boamah - One of the best experts on this subject based on the ideXlab platform.
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DNA Adducts of Decarbamoyl Mitomycin C Efficiently Kill Cells without Wild-Type p53 Resulting from Proteasome-Mediated Degradation of Checkpoint Protein 1
Chemical research in toxicology, 2010Co-Authors: Ernest K. Boamah, Angelika Brekman, Maria Tomasz, Natura Myeku, Maria E. Figueiredo-pereira, Senyene E. Hunter, Joel N. Meyer, R. Bhosle, Jill BargonettiAbstract:The Mitomycin Derivative 10-decarbamoyl Mitomycin C (DMC) more rapidly activates a p53-independent cell death pathway than Mitomycin C (MC). We recently documented that an increased proportion of mitosene1-β-adduct formation occurs in human cells treated with DMC in comparison to those treated with MC. Here, we compare the cellular and molecular response of human cancer cells treated with MC and DMC. We find the increase in mitosene 1-β-adduct formation correlates with a condensed nuclear morphology and increased cytotoxicity in human cancer cells with or without p53. DMC caused more DNA damage than MC in the nuclear and mitochondrial genomes. Checkpoint 1 protein (Chk1) was depleted following DMC, and the depletion of Chk1 by DMC was achieved through the ubiquitin proteasome pathway since chemical inhibition of the proteasome protected against Chk1 depletion. Gene silencing of Chk1 by siRNA increased the cytotoxicity of MC. DMC treatment caused a decrease in the level of total ubiquitinated proteins with...
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Abstract #5366: The N2-deoxyguanosine adducts of Mitomycins with mitosene-1-\#914; stereochemistry efficiently kill cells with compromised p53 through proteasome-mediated degradation of Chk1
Cancer Research, 2009Co-Authors: Ernest K. Boamah, Angelika Brekman, Maria Tomasz, Natura Myeku, Maria Figueredo-pereira, Jill BargonettiAbstract:Despite the importance of p53-independent cell death, little is known about the activation of such pathways. At least 50 percent of all cancers do not have a functional p53-pathway. We see that the Mitomycin Derivative 10-decarbamoyl Mitomycin C (DMC), in contrast to Mitomycin C (MC), can rapidly activate a p53-independent cell death pathway, which lacks markers for activation of an apoptotic death pathway. We recently reported that MC and DMC induce cellular cytotoxicity in human cells with wild-type p53, while only DMC shows significant cell death activity in the absence of wild-type p53. Nevertheless, it was unclear if the difference in cell death activity was due to the observed ability of DMC to form the alternative stereoisomeric 1-\#946; mono and 1-\#946; cross-link DNA adducts of guanine in human cell lines resulting in differential molecular signaling. In this study, we compared the DNA adducts and the cellular regulation of molecular targets upon treatment with MC and DMC in human cancer cell lines with or without wild-type p53. Compared to MC, DMC treatment produced substantially more 1-\#946; mono- and 1-\#946; cross-link DNA adducts, as measured by liquid chromatography/electrospray tandem mass spectrometry (Paz et al. Chem. Res.Toxicol., In Press). In addition, DMC-treatment resulted in abnormal nuclear morphology and increased cytotoxicity in human cancer cells with compromised p53 activity. We further established that DMC provoked a p53-independent cell death pathway that correlates with the formation of novel stereoisomeric DNA-adducts leading to down-regulation of Chk-1. Interestingly, Chk1 depletion was prevented by inhibition of the ubiquitin proteasome pathway, suggesting that DMC-DNA adducts may activate this proteolytic pathway. However, the observed decrease in the levels of ubiquitinated proteins upon DMC treatment was not caused by a direct change in proteasome activity suggesting that changed kinase signaling might be the cause of an activated pathway. Both MC and DMC have similar cytotoxicity upon depletion of Chk1 by siRNA, implicating loss of Chk1 as an important component in the DNA damage induced cell death pathway. In summary, we demonstrated that DMC generates significantly more mitosene-1-\#946; stereoisomeric DNA adducts than MC and causes down-regulation of Chk1 through the ubiquitin proteasome pathway. These studies suggest that mitosene-1-\#946; guanine adducts of DNA induce rapid and effective cell death of cancers with compromised p53, a cell type not rapidly killed by MC. This work was supported by a NIH SCORE Grant (1SC1CA137843-01), The Breast Cancer Research Foundation and was facilitated by a NIH Research Centers in Minority Institutions award from the Division of Research Resources (RR-03037) to Hunter College. EB is supported by the MBRS-RISE minority program at Hunter College. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5366.
Martin Highley - One of the best experts on this subject based on the ideXlab platform.
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Intravesical Drug Delivery
Clinical Pharmacokinetics, 1999Co-Authors: Martin Highley, Robert A. A. Maes, Allan T. Oosterom, Ernst A. De BruijnAbstract:Intravesical drug administration is widely used in the treatment of patients with superficial bladder cancer, and aims to optimise drug delivery in the vicinity of the tumour and reduce systemic availability. The most commonly employed intravesical agents in patients with superficial bladder cancer are Mitomycin (Mitomycin C), thiotepa, etoglucid (ethoglucid), anthracyclines such as doxorubicin, bacille Calmette-Guérin (BCG) and, more recently, taxol and the new Mitomycin Derivative KW-2149. Recurrence rates in patients with superficial bladder cancer have been substantially reduced by combined transurethral resection and intravesical pharmacotherapy. The high concentration of cytotoxics in urine and tumour tissue explain the high efficacy rates. Furthermore, the low systemic availability of most intravesical agents is consistent with the low frequency of acute and delayed systemic adverse effects. Systemic toxicity is almost negligible, except in the case of thiotepa, and local toxicity is transient and tolerable. Pharmacokinetic models of drug absorption from the bladder have been developed, both in animals and humans. These have led to the identification of optimal intravescial treatment regimens.
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Intravesical drug delivery. Pharmacokinetic and clinical considerations.
Clinical pharmacokinetics, 1999Co-Authors: Martin Highley, Allan T. Van Oosterom, Robert A. A. Maes, Ernst A. De BruijnAbstract:Intravesical drug administration is widely used in the treatment of patients with superficial bladder cancer, and aims to optimise drug delivery in the vicinity of the tumour and reduce systemic availability. The most commonly employed intravesical agents in patients with superficial bladder cancer are Mitomycin (Mitomycin C), thiotepa, etoglucid (ethoglucid), anthracyclines such as doxorubicin, bacille Calmette-Guerin (BCG) and, more recently, taxol and the new Mitomycin Derivative KW-2149.
Angelika Brekman - One of the best experts on this subject based on the ideXlab platform.
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DNA Adducts of Decarbamoyl Mitomycin C Efficiently Kill Cells without Wild-Type p53 Resulting from Proteasome-Mediated Degradation of Checkpoint Protein 1
Chemical research in toxicology, 2010Co-Authors: Ernest K. Boamah, Angelika Brekman, Maria Tomasz, Natura Myeku, Maria E. Figueiredo-pereira, Senyene E. Hunter, Joel N. Meyer, R. Bhosle, Jill BargonettiAbstract:The Mitomycin Derivative 10-decarbamoyl Mitomycin C (DMC) more rapidly activates a p53-independent cell death pathway than Mitomycin C (MC). We recently documented that an increased proportion of mitosene1-β-adduct formation occurs in human cells treated with DMC in comparison to those treated with MC. Here, we compare the cellular and molecular response of human cancer cells treated with MC and DMC. We find the increase in mitosene 1-β-adduct formation correlates with a condensed nuclear morphology and increased cytotoxicity in human cancer cells with or without p53. DMC caused more DNA damage than MC in the nuclear and mitochondrial genomes. Checkpoint 1 protein (Chk1) was depleted following DMC, and the depletion of Chk1 by DMC was achieved through the ubiquitin proteasome pathway since chemical inhibition of the proteasome protected against Chk1 depletion. Gene silencing of Chk1 by siRNA increased the cytotoxicity of MC. DMC treatment caused a decrease in the level of total ubiquitinated proteins with...
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Abstract #5366: The N2-deoxyguanosine adducts of Mitomycins with mitosene-1-\#914; stereochemistry efficiently kill cells with compromised p53 through proteasome-mediated degradation of Chk1
Cancer Research, 2009Co-Authors: Ernest K. Boamah, Angelika Brekman, Maria Tomasz, Natura Myeku, Maria Figueredo-pereira, Jill BargonettiAbstract:Despite the importance of p53-independent cell death, little is known about the activation of such pathways. At least 50 percent of all cancers do not have a functional p53-pathway. We see that the Mitomycin Derivative 10-decarbamoyl Mitomycin C (DMC), in contrast to Mitomycin C (MC), can rapidly activate a p53-independent cell death pathway, which lacks markers for activation of an apoptotic death pathway. We recently reported that MC and DMC induce cellular cytotoxicity in human cells with wild-type p53, while only DMC shows significant cell death activity in the absence of wild-type p53. Nevertheless, it was unclear if the difference in cell death activity was due to the observed ability of DMC to form the alternative stereoisomeric 1-\#946; mono and 1-\#946; cross-link DNA adducts of guanine in human cell lines resulting in differential molecular signaling. In this study, we compared the DNA adducts and the cellular regulation of molecular targets upon treatment with MC and DMC in human cancer cell lines with or without wild-type p53. Compared to MC, DMC treatment produced substantially more 1-\#946; mono- and 1-\#946; cross-link DNA adducts, as measured by liquid chromatography/electrospray tandem mass spectrometry (Paz et al. Chem. Res.Toxicol., In Press). In addition, DMC-treatment resulted in abnormal nuclear morphology and increased cytotoxicity in human cancer cells with compromised p53 activity. We further established that DMC provoked a p53-independent cell death pathway that correlates with the formation of novel stereoisomeric DNA-adducts leading to down-regulation of Chk-1. Interestingly, Chk1 depletion was prevented by inhibition of the ubiquitin proteasome pathway, suggesting that DMC-DNA adducts may activate this proteolytic pathway. However, the observed decrease in the levels of ubiquitinated proteins upon DMC treatment was not caused by a direct change in proteasome activity suggesting that changed kinase signaling might be the cause of an activated pathway. Both MC and DMC have similar cytotoxicity upon depletion of Chk1 by siRNA, implicating loss of Chk1 as an important component in the DNA damage induced cell death pathway. In summary, we demonstrated that DMC generates significantly more mitosene-1-\#946; stereoisomeric DNA adducts than MC and causes down-regulation of Chk1 through the ubiquitin proteasome pathway. These studies suggest that mitosene-1-\#946; guanine adducts of DNA induce rapid and effective cell death of cancers with compromised p53, a cell type not rapidly killed by MC. This work was supported by a NIH SCORE Grant (1SC1CA137843-01), The Breast Cancer Research Foundation and was facilitated by a NIH Research Centers in Minority Institutions award from the Division of Research Resources (RR-03037) to Hunter College. EB is supported by the MBRS-RISE minority program at Hunter College. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5366.