bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Histone Deacetylase Inhibitors in the Treatment of Thyroid Cancer
Authors: Mitsiades Constantine S. , Poulaki Vassiliki , McMullan Ciaran , Negri Joseph , Fanourakis Galinos , Goudopoulou Athina , Richon Victoria M. , Marks Paul A. , Mitsiades Nicholas 
Published: September 2005

Abstract
Histone deacetylases (HDAC) and histone acetyltransferases exert opposing enzymatic activities that modulate the degree of acetylation of histones and other intracellular molecular targets, thereby regulating gene expression, cellular differentiation, and survival. HDAC inhibition results in accumulation of acetylated histones and induces differentiation and/or apoptosis in transformed cells. In this study, we characterized the effect of two HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and m-carboxycinnamic acid bis-hydroxamide, on thyroid carcinoma cell lines, including lines originating from anaplastic and medullary carcinomas. In these models, both SAHA and m-carboxycinnamic acid bis-hydroxamide induced growth arrest and caspase-mediated apoptosis and increased p21 protein levels, retinoblastoma hypophosphorylation, BH3-interacting domain death agonist cleavage, Bax up-regulation, down-regulation of Bcl-2, A1, and Bcl-xL expression, and cleavage of poly(ADP-ribose) polymerase and caspase-8, -9, -3, -7, and -2. Transfection of Bcl-2 cDNA partially suppressed SAHA-induced cell death. SAHA down-regulated the expression of the apoptosis inhibitors FLIP and cIAP-2 and sensitized tumor cells to cytotoxic chemotherapy and death receptor activation. Our studies provide insight into the tumor type–specific mechanisms of antitumor effects of HDAC inhibitors and a framework for future clinical applications of HDAC inhibitors in patients with thyroid cancer, including histologic subtypes (e.g., anaplastic and medullary thyroid carcinomas) for which limited, if any, therapeutic options are available.
Antiangiogenic Properties of 17-(Dimethylaminoethylamino)-17-Demethoxygeldanamycin
Authors: Kaur Gurmeet , Belotti Dorina , Burger Angelika M. , Fisher-Nielson Kirsten , Borsotti Patrizia , Riccardi Elena , Thillainathan Jagada , Hollingshead Melinda , Sausville Edward A. , Giavazzi Raffaella 
Published: September 2005

Abstract
Purpose: The purpose of this study was to investigate the antiangiogenic properties of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG; NSC707545), a water-soluble benzoquinone ansamycin.
Experimental Design: The activity of 17-DMAG, in vivo, was evaluated for inhibition of fibroblast growth factor (FGF)-2-induced angiogenesis in s.c. implanted Matrigel in mice. In vitro, the activity of 17-DMAG on endothelial cells (human umbilical vein endothelial cells; HUVEC) was tested in FGF-2; and vascular endothelial growth factor (VEGF)-induced proliferation and apoptosis, motility, and extracellular matrix invasion; and on the alignment of capillary like structures in Matrigel. The protein level of heat shock protein (Hsp)90 and client proteins was examined by Western blot in FGF-2 and VEGF-stimulated HUVEC.
Results: Daily oral administration of 17-DMAG affected the angiogenic response in Matrigel in a dose-dependent manner. The hemoglobin content in the Matrigel implants was significantly inhibited, and the histological analysis confirmed a decrease of CD31+ endothelial cells and of structures organized in cord and erythrocyte-containing vessels. In vitro, the compound inhibited dose-dependently the migration and the extracellular matrix-invasiveness of HUVEC and their capacity to form capillary like structures in Matrigel. 17-DMAG treatment also inhibited FGF-2 and VEGF-induced HUVEC proliferation and resulted in apoptosis. Accordingly, the expression of Hsp90 direct client proteins (pAkt and c-Raf-1) or their downstream substrates including pERK was also affected. 17-DMAG consistently increased the expression of Hsp70. Throughout the study similar results were obtained with 17-allylamino-17-demethoxygeldanamycin (17-AAG; NSC330507), the analog compound currently undergoing clinical trials.
Conclusions: We show that the Hsp90 targeting agents 17-DMAG and 17-AAG inhibit angiogenesis. The strong effects on endothelial cell functions, in vitro, indicate that the antiangiogenic activity of 17-DMAG/17-AAG could also be due to a direct effect on endothelial cells. The oral bioavailability of 17-DMAG might be of advantage in investigating the potential of this compound in clinical trials with antiangiogenic as well as antiproliferative endpoints.
Genetic and Epigenetic Changes in
p21
and
p21B
Do Not Correlate with Resistance to Doxorubicin or Mitomycin and 5-Fluorouracil in Locally Advanced Breast Cancer
Authors: Staalesen Vidar , Leirvaag Beryl , Lillehaug Johan Richard , Lønning Per Eystein 
Published: September 2005

Abstract
Purpose: The cyclin-dependent kinase inhibitor p21 acts as a main executor of p53-induced growth arrest. Recently, a second transcript, p21B, was found to code for a protein expressing proapoptotic activity. We investigated p21 and p21B for mutations and epigenetic silencing in locally advanced breast cancers treated with doxorubicin or 5-fluorouracil/mitomycin and correlated our findings with treatment response and TP53 status.
Experimental Design: We used reverse transcription-PCR to analyze p21/p21B mutation status in 73 breast cancer samples. The p21 promoter region was sequenced and analyzed for hypermethylations by methylation-specific PCR. In addition, a selection of patients were analyzed for mutations in the p21B promoter.
Results: The p21 gene was neither mutated nor silenced by promoter hypermethylation in any of the tumors examined. One patient harbored a novel p21 splice variant in addition to the wild-type transcript. We observed two base substitutions in the p21 transcript, C93A and G251A, each affecting six patients (8.2%). The G251A variant had not been reported previously. In 12 patients (16.4%), we observed a novel base substitution, T35C, in p21B. All three base substitutions were observed in lymphocyte DNA and therefore considered polymorphisms. The polymorphisms did not correlate with p21 staining index, treatment response to doxorubicin or 5-fluorouracil/mitomycin, or TP53 status.
Conclusions: Our findings do not suggest that genetic or epigenetic disturbances in p21 or p21B cause resistance to doxorubicin or mitomycin/5-fluorouracil in breast cancer. Future studies should assess potential associations between these novel polymorphisms and breast cancer risk.
Enhanced Activity of Hu14.18-IL2 Immunocytokine against Murine NXS2 Neuroblastoma when Combined with Interleukin 2 Therapy
Authors: Neal Zane C. , Yang Jeannie C. , Rakhmilevich Alexander L. , Buhtoiarov Ilia N. , Lum Hillary E. , Imboden Michael , Hank Jacquelyn A. , Lode Holger N. , Reisfeld Ralph A. , Gillies Stephen D. , Sondel Paul M. 
Published: September 2005

AbstractEstablished s.c. NXS2 murine neuroblastoma tumors exhibited transient resolution after suboptimal therapy using the hu14.18-IL2 immunocytokine (IC). The hu14.18-IL2 IC is a fusion protein that has linked a molecule of interleukin 2 (IL-2) to the COOH terminus of each of the IgG heavy chains on the humanized anti-GD2 monoclonal antibody hu14.18. To induce more potent and longer lasting in vivo antitumor effects, we tested hu14.18-IL2 IC in a regimen combining it with constant infusion IL-2 in NXS2 tumor-bearing mice. The addition of the constant infusion IL-2 augmented the antitumor response induced by treatment with the hu14.18-IL2 IC in animals with experimentally induced hepatic metastases and in animals bearing localized s.c. tumors. The combined treatment induced prolonged tumor eradication in most animals bearing s.c. tumors and involved both natural killer cells and T cells. The enhanced ability of this combined treatment to prevent tumor recurrence was not observed when a larger dose of hu14.18-IL2 IC, similar in IL-2 content to the IC plus systemic IL-2 regimen, was tested as single-agent therapy. Animals showing prolonged tumor eradication of established tumors after the combined hu14.18-IL2 plus IL-2 regimen exhibited a protective T-cell-dependent antitumor memory response against NXS2 rechallenge.
The Tumor-Associated Antigen
PRAME
Is Universally Expressed in High-Stage Neuroblastoma and Associated with Poor Outcome
Authors: Oberthuer André , Hero Barbara , Spitz Rüdiger , Berthold Frank , Fischer Matthias 
Published: September 2005

Abstract
Purpose: The tumor-associated antigen PRAME, a potential candidate for immunotherapeutic targeting, is frequently expressed in a variety of cancers. However, no information about its presence in neuroblastoma is available to date. We therefore evaluated and quantified PRAME expression in a considerable number of neuroblastoma tumors and assessed its impact on the outcome of patients.
Experimental Design: Qualitative analysis of PRAME expression was assessed by reverse transcription (RT)-PCR screening of 94 patients with primary neuroblastoma. The same cohort was used for semiquantitative determination of transcript levels by Northern blotting, comparing the signal intensities of patients with those of testis total RNA. For more precise quantification of PRAME expression, real-time RT-PCR was performed in 88 patients of the above cohort and 7 additional patients, thus leaving a total of 101 patients that were analyzed with either method. Furthermore, association with tumor stage, age of patients at diagnosis, and MYCN amplification was determined as well as the prognostic impact of PRAME expression.
Results: RT-PCR screening detected PRAME expression in 93% of primary neuroblastoma and 100% of patients with advanced disease. Furthermore, RT-PCR and Northern blot analysis showed a highly significant association of PRAME expression with both higher tumor stage (P &lt; 0.01) and the age of patients at diagnosis (P &lt; 0.01). Finally, precise quantification of PRAME expression by quantitative real-time reverse transcription-PCR displayed significant impact on the outcome of patients.
Conclusions: PRAME expression in neuroblastoma is extraordinarily common and was universally seen in patients with advanced-stage disease in our study. Furthermore, significant impact of PRAME expression on the outcome of patients was shown. Thus, PRAME may present a particularly attractive target for immunotherapeutic strategies in neuroblastoma.
Vascular Endothelial Growth Factor-Trap Suppresses Tumorigenicity of Multiple Pancreatic Cancer Cell Lines
Authors: Fukasawa Mitsuharu , Korc Murray 
Published: September 2005

Abstract
Purpose: Vascular endothelial growth factor A (VEGF-A) is a potent angiogenic agent that binds to two high affinity VEGF receptors (VEGFRs), a process facilitated by the low affinity neuropilin receptors. Although VEGF-A is overexpressed in pancreatic ductal adenocarcinoma, it is not known whether the in vivo growth of multiple pancreatic cancer cells can be efficiently blocked by VEGF-A sequestration.
Experimental Design: Four human pancreatic cancer cell lines were grown s.c. in athymic nude mice. One cell line also was used to generate an orthotopic model of metastatic pancreatic cancer. The consequences of VEGF-A sequestration on tumor growth and metastasis were examined by injecting the mice with a soluble VEGFR chimer (VEGF-Trap) that binds VEGF-A with high affinity.
Results: VEGF-Trap, initiated 2 days after tumor cell inoculation, suppressed the s.c. growth of four pancreatic cancer cell lines and markedly decreased tumor microvessel density. Analysis of RNA from tumors generated with T3M4 cells revealed that VEGF-Trap decreased the expression of VEGFR-1 and neuropilin-1 and -2. VEGF-Trap, initiated 3 weeks after tumor implantation, also attenuated intrapancreatic tumor growth and metastasis in an orthotopic model using PANC-1 cells.
Conclusions: VEGF-Trap is a potent suppressor of pancreatic tumor growth and metastasis and also may act to attenuate neuropilin-1 and -2 and VEGFR-1 expression. Therefore, VEGF-Trap may represent an exceedingly useful therapeutic modality for pancreatic ductal adenocarcinoma.
Id-1 and Id-2 Proteins as Molecular Markers for Human Prostate Cancer Progression
Authors: Coppe Jean-Philippe , Itahana Yoko , Moore Dan H. , Bennington James L. , Desprez Pierre-Yves 
Published: September 2005

Abstract
Purpose: Id proteins are dominant-negative regulators of basic helix-loop-helix transcription factors that control malignant cell behavior in many different tissues. This study aimed to identify the potential role of Id-1 and Id-2 proteins as molecular makers for prostate cancer progression.
Experimental Design: Using the technique of immunohistochemistry, we determined Id-1 and Id-2 expression in a panel of 67 human prostate biopsies. We also manipulated Id-1 and Id-2 expression in LNCaP and PC3 prostate cancer cell lines and determined the effects on invasion in vitro, matrix metalloproteinase secretion, and proliferation.
Results: Both Id-1 and Id-2 proteins were up-regulated during human prostate cancer progression in vivo and were overexpressed in highly aggressive prostate cancer cells. In vitro, constitutive expression of Id-1, and to a lesser extent Id-2, converted nonaggressive LNCaP prostate cancer cells into more proliferative and invasive cells and increased their secretion of matrix metalloproteinases. Conversely, the down-regulation of Id-2 expression in highly metastatic PC3 cells reduced their growth potential and invasiveness.
Conclusions: We propose that both Id-1 and Id-2 proteins control prostate cancer cell phenotypes and could serve as molecular markers of aggressive human prostate cancer.
Up-regulation of p21 Gene Expression by Peroxisome Proliferator-Activated Receptor γ in Human Lung Carcinoma Cells
Authors: Han Shouwei , Sidell Neil , Fisher Paul B. , Roman Jesse 
Published: September 2005

Abstract
Purpose: The peroxisome proliferator-activated receptor γ (PPARγ), a ligand-dependent transcription factor belonging to the family of nuclear receptors, has been implicated in the regulation of cell growth and differentiation although the exact mechanism(s) of this activity has not been elucidated. In this study, we explored the role of PPARγ signaling on the control of gene expression of the cycle-dependent kinase inhibitor p21 in human lung carcinoma cells.
Experimental Design: Using several human lung carcinoma cell lines (small and non-small carcinoma cells), we assayed for cell growth inhibition and apoptosis induction. We also assayed for p21 mRNA and protein expression by reverse transcription-PCR, real-time reverse transcription-PCR, and Western blot analysis. Nuclear protein binding activities to three response elements located in the p21 promoter [nuclear factor (NF)-κB, Sp1, and NF-interleukin 6 (IL6) CAAT/enhancer binding protein (C/EBP)] were measured by gel mobility shift assays. We used transient transfection assays with p21 promoter reporter gene constructs to determine the transcriptional regulation by PPARγ ligands. Finally, by using p21 antisense oligonucleotides, we tested the link between PPARγ activation and p21 signaling in cell growth inhibition assays and by Western blot analysis.
Results: We showed that the PPARγ ligands PGJ2 and ciglitazone inhibit the growth and induce the apoptosis of several human lung carcinoma cell lines, whereas the PPARα agonist WY14643 has little effect. Treatment of lung carcinoma cells with the PPARγ ligands PGJ2, ciglitazone, troglizaone, and GW1929 elevated p21 mRNA and protein levels and reduced cyclin D1 mRNA levels. These results were supported by transient transfection assays, which indicated that PPARγ ligands increased p21 gene promoter activity in human lung carcinoma cells. In addition, p21 antisense oligonucleotides inhibited PPARγ ligand-induced p21 protein expression and significantly blocked lung carcinoma cell growth inhibition induced by PPARγ ligands. Finally, electrophoresis mobility shift experiments demonstrated that PPARγ ligands increased the nuclear binding activities of Sp1 and NF-IL6 (C/EBP), two transcription factors with regulatory elements in the promoter region of the p21 gene.
Conclusion: PPARγ ligands inhibit human lung carcinoma cell growth and induce apoptosis by stimulating the cyclin-dependent kinase inhibitor p21 and by reducing cyclin D1 gene expression. The induction of p21 gene expression by PPARγ ligands may be mediated through increased Sp1- and NF-IL6 (C/EBP)-dependent transcriptional activation. These observations unveil a mechanism for p21 gene regulation in lung carcinoma that represents a potential target for therapy.
Immunohistochemical Assessment of the Peripheral Benzodiazepine Receptor in Breast Cancer and Its Relationship with Survival
Authors: Galiègue Sylvaine , Casellas Pierre , Kramar Andrew , Tinel Norbert , Simony-Lafontaine Joelle 
Published: September 2005

Abstract
Purpose: The peripheral benzodiazepine receptor (PBR) expression has been shown dramatically increased in neoplastic tissues and tumor cell lines originated from ovary, liver, colon, breast, or brain relative to untransformed tissues. Its expression has been also associated with tumor progression and aggressiveness. To explore whether PBR expression level could be of prognostic value in invasive breast cancer, we studied a series of 117 patients who underwent surgery for primary breast carcinomas and were followed-up for 8 years.
Experimental Design: Using an immunohistochemical approach, we first compared PBR expression in normal and tumoral tissues, then we studied PBR expression together with clinicopathological variables (histological type, histological grade, lymph node, estrogen and progesterone receptor status), and biological markers such as BclII, Ki-67, and HER2/Neu.
Results: Our results revealed a significant increase of PBR expression in tumoral versus normal breast cells. We found a negative correlation between PBR expression and estrogen receptor status (P = 0.03) as well as a positive correlation between PBR and Ki-67 (P = 0.044). Although the disease-free survival was not affected by PBR in the whole population, high PBR expression level was significantly correlated with a shorter disease-free survival in the lymph node-negative patients, P = 0.038.
Conclusions: As the axillary lymph node-negative status is generally considered as a good prognosis factor, the high expression of PBR in this patient subgroup may be used to identify a new high risk population, for which a more specific therapy would be beneficial.
Murine Endothelial Cell Lines as Models of Tumor Endothelial Cells
Authors: Walter-Yohrling Jennifer , Morgenbesser Sharon , Rouleau Cecile , Bagley Rebecca , Callahan Michelle , Weber William , Teicher Beverly A. 
Published: September 2005

AbstractIdentification of appropriate models for in vivo and in vitro preclinical testing of inhibitors of tumor angiogenesis and progression is vital to the successful development of anticancer therapeutics. Although the focus is on human molecular targets, most preclinical in vivo efficacy testing occurs in mice. The goal of the current studies was to identify a murine endothelial cell line to model tumor endothelium for studying the antiangiogenic activity of therapeutic compounds in vitro. In situ hybridization was performed on three s.c. grown syngeneic murine tumors (B16 melanoma, Lewis lung carcinoma, and CT26 colon carcinoma) to assess expression of murine homologs of human tumor endothelial cell markers in the vasculature of these tumor models. Seven murine endothelial cell lines were characterized for expression of the murine homologs of recognized endothelial cell surface markers as well as for tumor endothelial cell surface markers. The seven murine endothelial cell lines had similar generation times and five of the seven lines were able to form tubes on Matrigel. Real-time-PCR and flow cytometry analysis were used to evaluate relative mRNA and protein expression of murine homologs of several recognized endothelial cell surface markers in the seven cell lines. The expression of the mRNA for the murine homologs of five tumor endothelial cell surface markers was also evaluated. The 2H11 cell line expressed all five of the tumor endothelial cell surface markers as well as several well-recognized endothelial cells markers. The 2H11 cell line responds to known and novel antiangiogenic agents by inhibition of proliferation and tube formation. These cells can be used in in vitro angiogenesis assays for evaluating the potential antiangiogenic properties and interspecies cross-reactivity of novel compounds.
Cdk Inhibitor p27Kip1 and Hormone Dependence in Breast Cancer
Authors: Arteaga Carlos L. 
Published: September 2005

Abstract
p27Kip1 is an important regulator of the G1 to S transition. While a potent inhibitor of cyclin-dependent-kinase (Cdk)2, p27 is also involved in assembly of cyclin D/Cdk4 complexes. Although rarely mutated, p27 is functionally downregulated in many human cancers by mechanisms involving enhanced degradation, cytoplasmic mislocalization, and/or sequestration by cyclin D/Cdk complexes in response to oncogenic signals. Therefore, low levels and/or cytoplasmic localized p27 have been associated with enhanced malignancy and poor patient prognosis in many neoplasias including breast cancer. Recent data discussed below suggest that a threshold of p27 is required for response to antiestrogens and, conversely, that low levels predict for antiestrogen resistance. These results imply that hormone receptor-positive tumors with low and/or cytosolic p27 respond poorly to antiestrogens and should be considered for alternative therapeutic strategies.
Nonendocrine Pathways and Endocrine Resistance
Authors: Nicholson Robert I. , Hutcheson Iain R. , Knowlden Janice M. , Jones Helen E. , Harper Maureen E. , Jordan Nicola , Hiscox Steve E. , Barrow Denise , Gee Julia M. W. 
Published: September 2005

Abstract
An increasing body of evidence demonstrates that growth factor networks are highly interactive with estrogen receptor signaling in the control of breast cancer growth. As such, tumor responses to antiestrogens are likely to be a composite of the estrogen receptor and growth factor-inhibitory activity of these agents, with alterations/aberrations in growth factor signaling providing a mechanism for the development of antiestrogen resistance. In this light, the current article focuses on illustrating the relationship between growth factor signaling and antiestrogen failure in our in-house tumor models of breast cancer and describing how we are now beginning to successfully target growth factor activity to improve the effects of antiestrogen drugs and to block aggressive disease progression.
Breast Cancer
Authors: Medina Daniel 
Published: September 2005

Abstract
It has been firmly established in epidemiological studies that early full-term pregnancy affords lifetime protection against the development of breast cancer. This phenomenon can be mimicked in rat and mouse models of mammary cancer in which the hormones estrogen and progesterone are given for 21 days. Carcinogen-induced proliferation is blocked as a consequence of hormone pretreatment. Among several genes implicated by molecular studies to be differentially expressed is the tumor suppressor gene p53. Both immunohistochemical and Western blot studies indicate that p53 protein expression is increased in hormone-pretreated mice and rats. The p53-regulated gene p21Cip1 is also increased concomitantly with p53. To test directly the causative role of p53 in conferring a protective phenotype, we examined the hormone-induced protective effect in BALB/c p53 null mammary epithelium. In the mammary epithelium, the absence of p53 gene expression abrogated the protective effect of prior pregnancy. The tumor incidence curves were superimposable in p53 null mammary epithelium that were treated with 7,12-dimethylbenzanthracene or pregnancy plus 7,12-dimethylbenzanthracene. These results demonstrate that p53 plays a pivotal role in hormone-induced protection and raises the question of the mechanisms by which the steroid hormones, estrogen and progesterone, functionally activate p53.