The Experts below are selected from a list of 204 Experts worldwide ranked by ideXlab platform
William W. Lamph - One of the best experts on this subject based on the ideXlab platform.
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Induction of adipocyte-specific gene expression is correlated with mammary tumor regression by the retinoid X receptor-ligand LGD1069 (targretin).
Cancer research, 2000Co-Authors: Veena R Agarwal, Eric D. Bischoff, Thomas W. Hermann, William W. LamphAbstract:Targretin (LGD1069; a high-affinity ligand for the retinoid X receptors) is an efficacious chemotherapeutic and chemopreventive agent in the N -nitroso- N -methylurea-induced rat mammary carcinoma model. To evaluate the molecular action of LGD1069 in mammary carcinoma we have examined gene expression patterns in controls and nonresponding tumors compared with tumors undergoing regression (responding) by LGD1069. When compared with controls or nonresponding tumors, the expression of adipocyte-related genes such as adipocyte P2 ( aP2 ), adipsin, peroxisome proliferator-activated receptor γ ( PPAR γ), and lipoprotein lipase was elevated in LGD1069-responding tumors. Further analysis showed that gene expression changes occurred rapidly, in as little as 6 h, after the first dose of LGD1069. Immunohistochemical analysis showed that aP2 protein was also highly expressed in responding tumors when compared with control or nonresponding tumors. More importantly, aP2 protein was localized in the tumor cells in addition to the adipocytes present in the tumors. Similar changes in gene expression and inhibition in growth were seen in tumor cells (cloned from N -nitroso- N -methylurea-induced carcinoma) exposed to LGD1069 in vitro . These data suggest that tumor regression by LGD1069 involves differentiation induction along the adipocyte lineage.
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Beyond tamoxifen: the retinoid X receptor-selective ligand LGD1069 (TARGRETIN) causes complete regression of mammary carcinoma.
Cancer research, 1998Co-Authors: Eric D. Bischoff, Marco M. Gottardis, Richard A. Heyman, Thomas E. Moon, William W. LamphAbstract:Abstract Recently, we reported that LGD1069, a high-affinity ligand for the retinoid X receptors (RXRs), was shown to have an efficacy equivalent to that of tamoxifen (TAM) as a chemopreventive agent in the N -nitroso- N -methylurea-induced rat mammary carcinoma model. Furthermore, LGD1069 was very well tolerated during 13 weeks of chronic therapy with no classic signs of “retinoid-associated” toxicities. Due to the high efficacy and benign profile of this RXR agonist as a suppressor of carcinogenesis, we examined its role as a therapeutic agent on established mammary carcinomas. In the rat mammary carcinoma model, N -nitroso- N -methylurea was used to induce tumors, and the tumors were allowed to grow to an established size prior to initiation of treatment. LGD1069-treated animals showed complete regression in 72% of treated tumors and had a reduced tumor load compared to control. In addition, the combination of LGD1069 and TAM showed increased efficacy over either agent alone. Histopathological analysis showed a reduction of LGD1069-treated tumor malignancy, an increase in differentiation, and a sharp decrease in cellular proliferation compared to vehicle-treated control tumors. These data demonstrate that the RXR-selective ligand LGD1069 is a highly efficacious therapeutic agent for mammary carcinoma and enhances the activity of TAM.
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Chemoprevention of Mammary Carcinoma by LGD1069 (Targretin): An RXR-selective Ligand
Cancer research, 1996Co-Authors: Marco M. Gottardis, Eric D. Bischoff, Michael A. Shirley, Murriel A. Wagoner, William W. Lamph, Richard A. HeymanAbstract:Recently, 9-cis retinoic acid, a high affinity ligand for retinoic acid receptors and retinoid X-receptors (RXRs), was shown to have efficacy superior to all-trans retinoic acid as a chemopreventive agent in the N-Nitroso-N-Methylurea-induced rat mammary carcinoma model. To further explore the specific contribution RXR activation may play in suppression of carcinogenesis, the efficacy of LGD1069 (Targretin), an RXR-selective ligand, in the N-Nitroso-N-Methylurea-induced rat mammary tumor model was studied. LGD1069-treated animals showed a 90% reduction in tumor burden and tumor incidence compared with vehicle-treated rats with an efficacy similar to that achieved with tamoxifen. LGD1069 was very well tolerated during 13 weeks of chronic therapy with no classic signs of "retinoid-associated" toxicities. These data demonstrate that LGD1069, an RXR-selective ligand, can act as a highly effective and benign chemopreventive agent for mammary carcinoma.
Michael B. Sporn - One of the best experts on this subject based on the ideXlab platform.
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Histogenesis of Induced Prostate and Seminal Vesicle Carcinoma in Lobund-Wistar Rats: A System for Histological Scoring and Grading
Cancer research, 1994Co-Authors: Michael V. Slayter, Mario A. Anzano, Kenji Kadomatsu, Joseph M. Smith, Michael B. SpornAbstract:We have developed a grading system for the evaluation of the histogenesis of neoplastic lesions of the prostate and seminal vesicle of the laboratory rat. Prostatic and seminal vesicle carcinomas were induced in Lobund-Wistar rats by initiation with 30 mg/kg N-Nitroso-N-Methylurea i.v., followed by promotion with 40 mg testosterone propionate implants 1 week later and at 3-month intervals thereafter. Experimental and control groups were sacrificed at various time points between 5 and 11 months after dosing with N-Nitroso-N-Methylurea in order to visualize progressive stages of carcinogenesis of the dorsolateral prostate, the anterior prostate, and the seminal vesicle. A system of staging was created which allows three different categories (in situ change, invasion, desmoplasia) of tumor development to be ranked progressively in a manner conducive to nonparametric analysis. Each category was then further subdivided to create a total of six stages. This system can be used to evaluate agents which modify tumor induction or suppression. The application of this staging system to the measurement of the effects of the synthetic retinoid, 4-hydroxyphenyl retinamide, on prostatic carcinogenesis in the Lobund-Wistar rat is described.
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Expression of Sulfated Glycoprotein 2 Is Associated with Carcinogenesis Induced by N-Nitroso-N-Methylurea in Rat Prostate and Seminal Vesicle
Cancer research, 1993Co-Authors: Kenji Kadomatsu, Michael V. Slayter, Mario A. Anzano, Joseph M. Smith, Thomas S. Winokur, Michael B. SpornAbstract:To understand the molecular mechanism of carcinogenesis in androgen-dependent tumors, we have searched for new markers which are associated with this process. In normal rat prostate and seminal vesicle, sulfated glycoprotein 2 (SGP-2) messenger RNA is barely detectable. However, we have found high levels of SGP-2 expression in the epithelial component of carcinomas of the prostate and seminal vesicle after initiation with N-Nitroso-N-Methylurea and promotion with testosterone propionate. We have also observed induction of SGP-2 expression in epithelial cells at early stages in carcinogenesis when cytologically malignant cells first begin to appear. SGP-2 has been reported previously to be associated with a variety of models of programmed cell death (apoptosis), including the prostate following castration. Our present findings provide a novel marker for carcinogenesis in the rat prostate and seminal vesicle.
Eric D. Bischoff - One of the best experts on this subject based on the ideXlab platform.
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Induction of adipocyte-specific gene expression is correlated with mammary tumor regression by the retinoid X receptor-ligand LGD1069 (targretin).
Cancer research, 2000Co-Authors: Veena R Agarwal, Eric D. Bischoff, Thomas W. Hermann, William W. LamphAbstract:Targretin (LGD1069; a high-affinity ligand for the retinoid X receptors) is an efficacious chemotherapeutic and chemopreventive agent in the N -nitroso- N -methylurea-induced rat mammary carcinoma model. To evaluate the molecular action of LGD1069 in mammary carcinoma we have examined gene expression patterns in controls and nonresponding tumors compared with tumors undergoing regression (responding) by LGD1069. When compared with controls or nonresponding tumors, the expression of adipocyte-related genes such as adipocyte P2 ( aP2 ), adipsin, peroxisome proliferator-activated receptor γ ( PPAR γ), and lipoprotein lipase was elevated in LGD1069-responding tumors. Further analysis showed that gene expression changes occurred rapidly, in as little as 6 h, after the first dose of LGD1069. Immunohistochemical analysis showed that aP2 protein was also highly expressed in responding tumors when compared with control or nonresponding tumors. More importantly, aP2 protein was localized in the tumor cells in addition to the adipocytes present in the tumors. Similar changes in gene expression and inhibition in growth were seen in tumor cells (cloned from N -nitroso- N -methylurea-induced carcinoma) exposed to LGD1069 in vitro . These data suggest that tumor regression by LGD1069 involves differentiation induction along the adipocyte lineage.
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Beyond tamoxifen: the retinoid X receptor-selective ligand LGD1069 (TARGRETIN) causes complete regression of mammary carcinoma.
Cancer research, 1998Co-Authors: Eric D. Bischoff, Marco M. Gottardis, Richard A. Heyman, Thomas E. Moon, William W. LamphAbstract:Abstract Recently, we reported that LGD1069, a high-affinity ligand for the retinoid X receptors (RXRs), was shown to have an efficacy equivalent to that of tamoxifen (TAM) as a chemopreventive agent in the N -nitroso- N -methylurea-induced rat mammary carcinoma model. Furthermore, LGD1069 was very well tolerated during 13 weeks of chronic therapy with no classic signs of “retinoid-associated” toxicities. Due to the high efficacy and benign profile of this RXR agonist as a suppressor of carcinogenesis, we examined its role as a therapeutic agent on established mammary carcinomas. In the rat mammary carcinoma model, N -nitroso- N -methylurea was used to induce tumors, and the tumors were allowed to grow to an established size prior to initiation of treatment. LGD1069-treated animals showed complete regression in 72% of treated tumors and had a reduced tumor load compared to control. In addition, the combination of LGD1069 and TAM showed increased efficacy over either agent alone. Histopathological analysis showed a reduction of LGD1069-treated tumor malignancy, an increase in differentiation, and a sharp decrease in cellular proliferation compared to vehicle-treated control tumors. These data demonstrate that the RXR-selective ligand LGD1069 is a highly efficacious therapeutic agent for mammary carcinoma and enhances the activity of TAM.
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Chemoprevention of Mammary Carcinoma by LGD1069 (Targretin): An RXR-selective Ligand
Cancer research, 1996Co-Authors: Marco M. Gottardis, Eric D. Bischoff, Michael A. Shirley, Murriel A. Wagoner, William W. Lamph, Richard A. HeymanAbstract:Recently, 9-cis retinoic acid, a high affinity ligand for retinoic acid receptors and retinoid X-receptors (RXRs), was shown to have efficacy superior to all-trans retinoic acid as a chemopreventive agent in the N-Nitroso-N-Methylurea-induced rat mammary carcinoma model. To further explore the specific contribution RXR activation may play in suppression of carcinogenesis, the efficacy of LGD1069 (Targretin), an RXR-selective ligand, in the N-Nitroso-N-Methylurea-induced rat mammary tumor model was studied. LGD1069-treated animals showed a 90% reduction in tumor burden and tumor incidence compared with vehicle-treated rats with an efficacy similar to that achieved with tamoxifen. LGD1069 was very well tolerated during 13 weeks of chronic therapy with no classic signs of "retinoid-associated" toxicities. These data demonstrate that LGD1069, an RXR-selective ligand, can act as a highly effective and benign chemopreventive agent for mammary carcinoma.
Helmut Zarbl - One of the best experts on this subject based on the ideXlab platform.
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Chemopreventive Doses of Methylselenocysteine Alter Circadian Rhythm in Rat Mammary Tissue
Cancer prevention research (Philadelphia Pa.), 2008Co-Authors: Xun Zhang, Helmut ZarblAbstract:It is known that organic forms of selenium inhibit chemically induced rat mammary carcinogenesis, although the molecular basis remains to be elucidated. To identify signaling pathways involved in carcinogenesis that are also modulated by methylselenocysteine, we compared the global gene expression profiles in mammary tissues from pubescent female rats maintained on a selenium-supplemented (3 ppm) diet with those on a standardized diet after N -nitroso- N -methylurea. Whereas the selenium-enriched diet altered the steady-state levels of genes involved in various cellular functions, the most dramatic effect was the coordinated changes in the expression of multiple genes that regulate circadian rhythm. Normal mammary tissue of rats fed a standardized diet showed little circadian oscillation relative to liver tissue. By contrast, mammary tissue of rats maintained on the selenium-enriched diet showed a progressive, time-dependent increase in the expression of circadian gene Per2 and circadian-regulated transcription factor DBP . Our results further showed that the expression of Per2 and DBP mRNAs was significantly decreased in mammary tumors arising in rats on the selenium-enriched diet, but not in tumors of rats on the control diet, suggesting that selenium-induced elevation in the expression of circadian genes was incompatible with mammary carcinogenesis. Given the previously reported role of Per2 as a tumor suppressor, these observations suggest that Per2 is an important target of methylselenocysteine during chemoprevention in N -nitroso- N -methylurea–induced rat mammary carcinogenesis, and for the first time provide a link between chemoprevention and circadian rhythm.
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Alterations in H-ras1 promoter conformation during N-Nitroso-N-Methylurea-induced mammary carcinogenesis and pregnancy.
Cancer research, 1996Co-Authors: Zhuang Jin, Benoit Houle, Andrei M. Mikheev, Rita S. Cha, Helmut ZarblAbstract:We previously demonstrated that H-ras1 oncogene mutations detected in N -nitroso- N -methylurea (NMU)-induced mammary tumors arose as background mutations within rat mammary cells (RMCs) and that NMU promoted the outgrowth of these preexisting mutants. We have now detected a putative DNA structure in the H-ras1 promoter of RMCs in vivo that was absent in NMU-induced mammary tumor cells. Analysis of the promoter in RMCs as a function of time after exposure to carcinogens indicated that NMU, but not 7,12-dimethylbenz( a )anthracene, initiated the loss of this structure with a half-life of 7 days. Although loss of the structure was irreversible in cells that gave rise to tumors, it was restored in normal RMCs by 120 days after exposure and was present in normal RMCs of animals bearing tumors, even 1 year after NMU exposure. The structure was also abrogated in RMCs during pregnancy and restored after lactation was terminated, suggesting that reversible regulation of the structure by hormones contributed to normal RMC growth. Thus, NMU may promote abnormal RMC growth by mimicking the effects of hormones on DNA conformation. We hypothesize that the NMU-induced alterations in promoter conformation irreversibly deregulates H-ras1 expression in initiated cells, thereby increasing the phenotypic penetrance of the conditional H-ras1 mutations.
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N-Nitroso-N-Methylurea-induced rat mammary tumors arise from cells with preexisting oncogenic Hras1 gene mutations.
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Rita S. Cha, William G. Thilly, Helmut ZarblAbstract:Abstract GGA to GAA mutations in the 12th codon of the Hras gene are frequently observed in rat mammary tumors induced by N-Nitroso-N-Methylurea (NMU). We developed an assay to measure point mutations present in tissues at a frequency of 10(-5) and have now applied this assay to measure the specific G to A transition of the Hras gene in rat mammary epithelium. We find that (i) 70% of untreated rats contain detectable levels of Hras mutants; (ii) these mutants are clustered within the gland as sectors in a manner consistent with their origin as a mutation arising during early organ development; and (iii) treatment with a carcinogenic dose of NMU did not result in a significant increase in the number of such mutants, the fraction of organ sectors with mutant cells, or the fraction of animals containing detectable levels of ras mutants. We conclude that the NMU-induced mammary tumors carrying the G to A transition at the 12th codon of the Hras gene arose from preexisting ras mutants and that an independent effect of NMU was directly or indirectly responsible for tumor formation.
Richard A. Heyman - One of the best experts on this subject based on the ideXlab platform.
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Beyond tamoxifen: the retinoid X receptor-selective ligand LGD1069 (TARGRETIN) causes complete regression of mammary carcinoma.
Cancer research, 1998Co-Authors: Eric D. Bischoff, Marco M. Gottardis, Richard A. Heyman, Thomas E. Moon, William W. LamphAbstract:Abstract Recently, we reported that LGD1069, a high-affinity ligand for the retinoid X receptors (RXRs), was shown to have an efficacy equivalent to that of tamoxifen (TAM) as a chemopreventive agent in the N -nitroso- N -methylurea-induced rat mammary carcinoma model. Furthermore, LGD1069 was very well tolerated during 13 weeks of chronic therapy with no classic signs of “retinoid-associated” toxicities. Due to the high efficacy and benign profile of this RXR agonist as a suppressor of carcinogenesis, we examined its role as a therapeutic agent on established mammary carcinomas. In the rat mammary carcinoma model, N -nitroso- N -methylurea was used to induce tumors, and the tumors were allowed to grow to an established size prior to initiation of treatment. LGD1069-treated animals showed complete regression in 72% of treated tumors and had a reduced tumor load compared to control. In addition, the combination of LGD1069 and TAM showed increased efficacy over either agent alone. Histopathological analysis showed a reduction of LGD1069-treated tumor malignancy, an increase in differentiation, and a sharp decrease in cellular proliferation compared to vehicle-treated control tumors. These data demonstrate that the RXR-selective ligand LGD1069 is a highly efficacious therapeutic agent for mammary carcinoma and enhances the activity of TAM.
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Chemoprevention of Mammary Carcinoma by LGD1069 (Targretin): An RXR-selective Ligand
Cancer research, 1996Co-Authors: Marco M. Gottardis, Eric D. Bischoff, Michael A. Shirley, Murriel A. Wagoner, William W. Lamph, Richard A. HeymanAbstract:Recently, 9-cis retinoic acid, a high affinity ligand for retinoic acid receptors and retinoid X-receptors (RXRs), was shown to have efficacy superior to all-trans retinoic acid as a chemopreventive agent in the N-Nitroso-N-Methylurea-induced rat mammary carcinoma model. To further explore the specific contribution RXR activation may play in suppression of carcinogenesis, the efficacy of LGD1069 (Targretin), an RXR-selective ligand, in the N-Nitroso-N-Methylurea-induced rat mammary tumor model was studied. LGD1069-treated animals showed a 90% reduction in tumor burden and tumor incidence compared with vehicle-treated rats with an efficacy similar to that achieved with tamoxifen. LGD1069 was very well tolerated during 13 weeks of chronic therapy with no classic signs of "retinoid-associated" toxicities. These data demonstrate that LGD1069, an RXR-selective ligand, can act as a highly effective and benign chemopreventive agent for mammary carcinoma.
