bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cytochrome P450 1B1 Expression in Glial Cell Tumors: An Immunotherapeutic Target
Authors: Barnett Julia A. , Urbauer Diana L. , Murray Graeme I. , Fuller Gregory N. , Heimberger Amy B. 
Published: June 2007

Abstract
Purpose: Among central nervous system malignancies, cytochrome P450 1B1 (CYP1B1) expression has only been characterized in medulloblastoma. An immunotherapeutic agent targeting this antigen was shown to safely stimulate a good immune response. To evaluate the viability of further research efforts targeting this antigen, we examined the expression of CYP1B1 in glial cell malignancies.
Experimental Design: We studied the frequency and extent of CYP1B1 expression by immunohistochemical analysis in 269 glial tumors (including all major pathologic types) on a tissue microarray. Results were categorized by percentage of cells stained and intensity of cytoplasmic staining within cells. Correlation of CYP1B1 expression with patient prognosis was evaluated by univariate and multivariate analyses.
Results: Overall, increased CYP1B1 expression in glial tumors was associated with decreased patient survival time (P &lt; 0.0014 for both percentage and intensity of staining). A significant difference existed in percentage and intensity of staining between astrocytic and oligodendroglial tumors (P = 0.0002 and 0.0003, respectively), between grades of tumors (P &lt; 0.0001 and 0.0079), and between pathologic types of tumors (P &lt; 0.0001 and 0.0339). Positive CYP1B1 staining was seen in 81% of glioblastomas, 84% of anaplastic astrocytomas, 61% of oligodendrogliomas, and 67% of anaplastic oligodendrogliomas. Paradoxically, within specific tumor pathologies, there was a trend toward increased survival as CYP1B1 expression increased. However, in the multivariate analysis, this trend disappeared, and CYP1B1 expression seemed prognostically neutral.
Conclusion: CYP1B1 is frequently expressed in a variety of gliomas and could be used as a target for immunotherapy.
Epidermal Growth Factor Receptor R497K Polymorphism Is a Favorable Prognostic Factor for Patients with Colorectal Carcinoma
Authors: Wang Wei-Shu , Chen Po-Min , Chiou Tzeon-Jye , Liu Jin-Hwang , Lin Jen-Kou , Lin Tzu-Chen , Wang Huann-Sheng , Su Yeu 
Published: June 2007

AbstractPurpose: It has been shown that the R497K polymorphism of the epidermal growth factor receptor (EGFR) has attenuated functions in ligand binding, tyrosine kinase activation, and growth stimulation. Because the activation of EGFR results in an unfavorable prognosis of patients with colorectal carcinoma, a pilot study was conducted to assess the influence of this polymorphism on colorectal carcinoma patients.Experimental Design: We retrospectively analyzed the effect of the R497K polymorphism of EGFR on clinicopathologic features in 209 colorectal carcinoma patients, including 100 with stage II/III colorectal carcinoma receiving curative surgery and the other 109 with metastatic diseases.Results: An excellent correlation in codon 497 statuses examined by patients' WBCs and tumor tissues was found but no significant between-group difference in patients with or without colorectal carcinoma (P = 0.97). A marked decrease on EGFR phosphorylation (P &lt; 0.01) and c-Myc activation (P = 0.02) was observed in patients with R497K polymorphism, which is associated with decreased invasion (P = 0.01), lower nodal involvement (P = 0.02), reduced subsequent metastasis (P &lt; 0.01), and longer disease-free (P &lt; 0.01) as well as overall (P &lt; 0.01) survival in stage II/III colorectal carcinoma patients who had received curative surgery. For patients with metastatic colorectal carcinoma, this polymorphism was associated with a higher response to 5-fluorouracil/oxaliplatin treatment (P = 0.02) and a longer survival (P &lt; 0.01). By multivariate analysis, this polymorphism was also identified as an independent prognostic factor (P = 0.03).Conclusions: These data suggest that the R497K polymorphism of the EGFR, by reducing its activation and a consequential down-regulation of its target genes, could be a key determinant for reduced tumor recurrence of stage II/III colorectal carcinoma patients receiving curative surgery and a longer survival of patients with stage II/III as well as metastatic colorectal carcinoma.
Promoter Hypermethylation of the Bone Morphogenetic Protein-6 Gene in Malignant Lymphoma
Authors: Daibata Masanori , Nemoto Yuiko , Bandobashi Kentaro , Kotani Norihiro , Kuroda Masayuki , Tsuchiya Mutsumi , Okuda Heiwa , Takakuwa Tetsuya , Imai Shosuke , Shuin Taro , Taguchi Hirokuni 
Published: June 2007

Abstract
Purpose: Bone morphogenetic proteins (BMP), belonging to the transforming growth factor-β superfamily, are important regulators of cell growth, differentiation, and apoptosis. The biological effects of BMPs on malignant lymphoma, however, remain unknown. Promoter methylation of the BMP-6 gene in lymphomas was investigated.
Experimental Design: We investigated BMP-6 promoter methylation and its gene expression in various histologic types of 90 primary lymphomas and 30 lymphoma cell lines. The effect of BMP-6 promoter hypermethylation on clinical outcome was also evaluated.
Results: BMP-6 was epigenetically inactivated in subsets of lymphomas. The silencing occurred with high frequency in diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma in association with aberrant BMP-6 promoter methylation. The methylation was observed in 60% (21 of 35) of DLBCL cases and 100% (7 of 7) of DLBCL cell lines, and in 83% (5 of 6) of Burkitt's lymphoma cases and 86% (12 of 14) of Burkitt's lymphoma cell lines. In contrast, other histologic types of primary lymphomas studied had little or no detectable methylation (1 of 49; 2%). The presence of BMP-6 promoter hypermethylation in DLBCL statistically correlated with a decrease in disease-free survival (P = 0.014) and overall survival (P = 0.038). Multivariate analysis showed that the methylation profile was an independent prognostic factor in predicting disease-free survival (P = 0.022) and overall survival (P = 0. 046).
Conclusion: BMP-6 promoter was hypermethylated more often in aggressive types of lymphomas, and the hypermethylation is likely to be related to the histologic type of lymphomas. BMP-6 promoter methylation may be a potential new biomarker of risk prediction in DLBCL.
Expression of Erythropoietin Receptor andIn vitroFunctional Effects of Epoetins in B-Cell Malignancies
Authors: Kokhaei Parviz , Abdalla Amir Osman , Hansson Lotta , Mikaelsson Eva , Kubbies Manfred , Haselbeck Anton , Jernberg-Wiklund Helena , Mellstedt Håkan , Österborg Anders 
Published: June 2007

AbstractPurpose: Erythropoietin (EPO) and EPO receptor (EPO-R) expression have been reported in solid tumors and are claimed to regulate tumor growth; however, no data have been published on this issue in B-cell malignancies or normal lymphoid cells. This report describes genomic/protein EPO-R expression and in vitro effects of recombinant human EPO (epoetin) in B-cell chronic lymphocytic leukemia (B-CLL), mantle-cell lymphoma (MCL), and multiple myeloma (MM).Experimental Design: Blood samples were obtained from patients with B-CLL, MCL, and healthy volunteers, and bone marrow was obtained from MM patients. EPO-R mRNA was detected by reverse transcription-PCR. EPO-R surface expression was investigated by flow cytometry using digoxigenin-labeled epoetin and polyclonal rabbit anti–EPO-R antibody for intracellular receptor. Tumor cell stimulation was determined in vitro using [3H]thymidine incorporation and CD69 expression after exposure to epoetin α or β or darbepoetin α.Results: EPO-R mRNA was detected in mononuclear cells from 32 of 41 (78%) B-CLL and 5 of 7 (71%) MCL patients, and 21 of 21 (100%) MM samples. Expression was also detected in highly purified T cells from six of eight B-CLL patients, four of four MM patients, and normal donor B and T cells. Surface EPO-R protein was not detected. Intracellular EPO-R staining with anti–EPO-R antibodies was unspecific. No tumor-stimulatory effect was observed with high epoetin concentrations.Conclusions: EPO-R gene is frequently expressed in lymphoid malignancies and normal B and T cells. However, there was no surface protein expression and no epoetin-induced in vitro stimulation of tumor B cells, indicating that epoetin therapy in vivo is likely to be safe in patients with lymphoid malignancies.
Lack of an Association between the TGFBR1*6A Variant and Colorectal Cancer Risk
Authors: Skoglund Johanna , Song Bo , Dalén Johan , Dedorson Stefan , Edler David , Hjern Fredrik , Holm Jörn , Lenander Claes , Lindforss Ulrik , Lundqvist Nils , Olivecrona Hans , Olsson Louise , Påhlman Lars , Rutegård Jörgen , Smedh Kennet , Törnqvist Anders , Houlston Richard S. , Lindblom Annika 
Published: June 2007

Abstract
Purpose: Recently a common variant of the TGFBR1 gene, TGFBR1*6A, has been proposed to act as a low-penetrance tumor susceptibility allele for colorectal cancer, but data from published studies with individually low statistical power are conflicting. To further evaluate the relationship between TGFBR1*6A and colorectal cancer risk, we have conducted a large case-control study and a meta-analysis of previously published studies.
Experimental Design: A total of 1,042 colorectal cancer cases and 856 population controls were genotyped for the TGFBR1*6A polymorphism. Previously published case-control studies of the relationship between TGFBR1*6A and colorectal cancer were identified, and a meta-analysis was conducted.
Results: We found no evidence that homozygosity, heterozygosity or carrier status for the TGFBR1*6A allele confers an increased risk of colorectal cancer; respective odds ratios (OR) were 1.05 [95% confidence interval (95% CI), 0.83-1.32], 0.82 (95% CI, 0.34-1.99), and 0.92 (95% CI, 0.74-1.15), respectively. A meta-analysis of our case-control study and seven other studies that provided data on 2,627 colorectal cancer cases and 3,387 controls also yielded no evidence that possession of the TGFBR1*6A allele is associated with an elevated risk of colorectal cancer; pooled estimate of the OR were 1.20 (95% CI, 0.64-2.24) for homozygosity, 1.11 (95% CI, 0.96-1.29) for heterozygosity, and 1.13 (95% CI, 0.98-1.30) for carriers of TGFBR1*6A.
Conclusion: Current data provide limited support for the hypothesis that sequence variation in TGFBR1 defined by the TGFBR1*6A allele confers an elevated risk of colorectal cancer.
[Lys40(Ahx-DTPA-111In)NH2]-Exendin-4 Is a Highly Efficient Radiotherapeutic for Glucagon-Like Peptide-1 Receptor–Targeted Therapy for Insulinoma
Authors: Wicki Andreas , Wild Damian , Storch Daniel , Seemayer Christian , Gotthardt Martin , Behe Martin , Kneifel Stefan , Mihatsch Michael J. , Reubi Jean-Claude , Mäcke Helmut R. , Christofori Gerhard 
Published: June 2007

Abstract
Purpose: Although metabolic changes make diagnosis of insulinoma relatively easy, surgical removal is hampered by difficulties in locating it, and there is no efficient treatment for malignant insulinoma. We have previously shown that the high density of glucagon-like peptide-1 receptors (GLP-1R) in human insulinoma cells provides an attractive target for molecular imaging and internal radiotherapy. In this study, we investigated the therapeutic potential of [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4, an 111In-labeled agonist of GLP-1, in a transgenic mouse model of human insulinoma.
Experimental Design: [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4 was assessed in the Rip1Tag2 mouse model of pancreatic β-cell carcinogenesis, which exhibits a GLP-1R expression comparable with human insulinoma. Mice were injected with 1.1, 5.6, or 28 MBq of the radiopeptide and sacrificed 7 days after injection. Tumor uptake and response, the mechanism of action of the radiopeptide, and therapy toxicity were investigated.
Results: Tumor uptake was &gt;200% injected activity per gram, with a dose deposition of 3 Gy/MBq at 40 pmol [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4. Other GLP-1R–positive organs showed ≥30 times lower dose deposition. A single injection of [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4 resulted in a reduction of the tumor volume by up to 94% in a dose-dependent manner without significant acute organ toxicity. The therapeutic effect was due to increased tumor cell apoptosis and necrosis and decreased proliferation.
Conclusions: The results suggest that [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4 is a promising radiopeptide capable of selectively targeting insulinoma. Furthermore, Auger-emitting radiopharmaceuticals such as 111In are able to produce a marked therapeutic effect if a high tumor uptake is achieved.
AZD1152, a Selective Inhibitor of Aurora B Kinase, Inhibits Human Tumor Xenograft Growth by Inducing Apoptosis
Authors: Wilkinson Robert W. , Odedra Rajesh , Heaton Simon P. , Wedge Stephen R. , Keen Nicholas J. , Crafter Claire , Foster John R. , Brady Madeleine C. , Bigley Alison , Brown Elaine , Byth Kate F. , Barrass Nigel C. , Mundt Kirsten E. , Foote Kevin M. , Heron Nicola M. , Jung Frederic H. , Mortlock Andrew A. , Boyle F. Thomas , Green Stephen 
Published: June 2007

Abstract
Purpose: In the current study, we examined the in vivo effects of AZD1152, a novel and specific inhibitor of Aurora kinase activity (with selectivity for Aurora B).
Experimental Design: The pharmacodynamic effects and efficacy of AZD1152 were determined in a panel of human tumor xenograft models. AZD1152 was dosed via several parenteral (s.c. osmotic mini-pump, i.p., and i.v.) routes.
Results: AZD1152 potently inhibited the growth of human colon, lung, and hematologic tumor xenografts (mean tumor growth inhibition range, 55% to ≥100%; P &lt; 0.05) in immunodeficient mice. Detailed pharmacodynamic analysis in colorectal SW620 tumor-bearing athymic rats treated i.v. with AZD1152 revealed a temporal sequence of phenotypic events in tumors: transient suppression of histone H3 phosphorylation followed by accumulation of 4N DNA in cells (2.4-fold higher compared with controls) and then an increased proportion of polyploid cells (&gt;4N DNA, 2.3-fold higher compared with controls). Histologic analysis showed aberrant cell division that was concurrent with an increase in apoptosis in AZD1152-treated tumors. Bone marrow analyses revealed transient myelosuppression with the drug that was fully reversible following cessation of AZD1152 treatment.
Conclusions: These data suggest that selective targeting of Aurora B kinase may be a promising therapeutic approach for the treatment of a range of malignancies. In addition to the suppression of histone H3 phosphorylation, determination of tumor cell polyploidy and apoptosis may be useful biomarkers for this class of therapeutic agent. AZD1152 is currently in phase I trials.
Restoration of Tissue Factor Pathway Inhibitor-2 in a Human Glioblastoma Cell Line Triggers Caspase-Mediated Pathway and Apoptosis
Authors: George Joseph , Gondi Christopher S. , Dinh Dzung H. , Gujrati Meena , Rao Jasti S. 
Published: June 2007

Abstract
Purpose: The induction of apoptotic pathways in cancer cells offers a novel and potentially useful approach to improve patient responses to conventional chemotherapy. Tissue factor pathway inhibitor-2 (TFPI-2) is a protease inhibitor that is abundant in the extracellular matrix and highly expressed in noninvasive cells but absent or undetectable in highly invasive human glioblastoma cells.
Experimental Design: Using a recombinant adeno-associated viral vector carrying human TFPI-2 cDNA, we stably expressed TFPI-2 in U-251 cells, a highly invasive human glioblastoma cell line. Our previous studies showed that restoration of TFPI-2 in glioblastomas effectively prevents cell proliferation, angiogenesis, and tumor invasion. In this study, we determined whether TFPI-2 restoration could induce apoptosis through the caspase-mediated signaling pathway.
Results: The results from nuclear chromatin staining, terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling assay, and fluorescence-activated cell sorting analysis showed increased apoptosis in U-251 cells after restoration of TFPI-2. Caspase-9 and caspase-3 activity assays showed increased activity, indicating enhanced apoptosis. Immunofluorescence for cleaved caspase-9 and caspase-3 depicted increased expression and colocalization of both molecules. Western blot analysis showed increased transcriptional activities of Fas ligand, tumor necrosis factor-α, Bax, Fas-associated death domain, and tumor necrosis factor receptor 1–associated death domain as well as elevated levels of cleaved caspases and poly(ADP-ribose) polymerase. Semiquantitative reverse transcription-PCR depicted increased expression of tumor necrosis factor-α and Fas ligand and the related death domains tumor necrosis factor receptor 1–associated death domain and Fas-associated death domain.
Conclusions: Taken together, these results show that restoration of TFPI-2 activates both intrinsic and extrinsic caspase-mediated, proapoptotic signaling pathways and induces apoptosis in U-251 cells. Furthermore, our study suggests that recombinant adeno-associated viral vector–mediated gene expression offers a novel tool for cancer gene therapy.
Proteomic Analysis Identifies Oxidative Stress Induction by Adaphostin
Authors: Stockwin Luke H. , Bumke Maja A. , Yu Sherry X. , Webb Simon P. , Collins Jack R. , Hollingshead Melinda G. , Newton Dianne L. 
Published: June 2007

Abstract
Purpose: Activities distinct from inhibition of Bcr/abl have led to adaphostin (NSC 680410) being described as “a drug in search of a mechanism.” In this study, proteomic analysis of adaphostin-treated myeloid leukemia cell lines was used to further elucidate a mechanism of action.
Experimental Design: HL60 and K562 cells treated with adaphostin for 6, 12, or 24 h were analyzed using two-dimensional PAGE. Differentially expressed spots were excised, digested with trypsin, and analyzed by liquid chromatography–tandem mass spectrometry. The contribution of the redox-active hydroquinone group in adaphostin was also examined by carrying out proteomic analysis of HL60 cells treated with a simple hydroquinone (1,4-dihydroxybenzene) or H2O2.
Results: Analysis of adaphostin-treated cells identified 49 differentially expressed proteins, the majority being implicated in the response to oxidative stress (e.g., CALM, ERP29, GSTP1, PDIA1) or induction of apoptosis (e.g., LAMA, FLNA, TPR, GDIS). Interestingly, modulation of these proteins was almost fully prevented by inclusion of an antioxidant, N-acetylcysteine. Validation of the proteomic data confirmed GSTP1 as an adaphostin resistance gene. Subsequent analysis of HL60 cells treated with 1,4-dihydroxybenzene or H2O2 showed similar increases in intracellular peroxides and an almost identical proteomic profiles to that of adaphostin treatment. Western blotting of a panel of cell lines identified Cu/Zn superoxide dismutase (SOD) as correlating with adaphostin resistance. The role of SOD as a second adaphostin resistance gene was confirmed by demonstrating that inhibition of SOD using diethyldithiocarbamate increased adaphostin sensitivity, whereas transfection of SOD I attenuated toxicity. Importantly, treatment with 1,4-dihydroxybenzene or H2O2 replicated adaphostin-induced Bcr/abl polypeptide degradation, suggesting that kinase inhibition is a ROS-dependent phenomenon.
Conclusion: Adaphostin should be classified as a redox-active–substituted dihydroquinone.
Differential Metabolism of Gefitinib and Erlotinib by Human Cytochrome P450 Enzymes
Authors: Li Jing , Zhao Ming , He Ping , Hidalgo Manuel , Baker Sharyn D. 
Published: June 2007

AbstractPurpose: To examine the enzyme kinetics of gefitinib and erlotinib metabolism by individual cytochrome P450 (CYP) enzymes, and to compare their effects on CYP3A activity, with the aim to better understand mechanisms underlying pharmacokinetic variability and clinical effects.Experimental Design: Enzyme kinetics were examined by incubating gefitinib or erlotinib (1.5-50 μmol/L) with recombinant human CYP3A4, CYP3A5, CYP2D6, CYP1A1, CYP1A2, and CYP1B1 (10-160 pmol/mL). Their effects on CYP3A activity were examined by comparing midazolam metabolism in the presence and absence of gefitinib or erlotinib in human liver and intestinal microsomes. Parent compounds and metabolites were monitored by high-performance liquid chromatography with a photodiode detector or tandem mass spectrometer.Results: Both drugs were metabolized primarily by CYP3A4, CYP3A5, and CYP1A1, with respective maximum clearance (Clmax) values for metabolism of 0.41, 0.39, and 0.57 mL/min/nmol for gefitinib and 0.24, 0.21, 0.31 mL/min/nmol for erlotinib. CYP2D6 was involved in gefitinib metabolism (Clmax, 0.63 mL/min/nmol) to a large extent, whereas CYP1A2 was considerably involved in erlotinib metabolism (Clmax, 0.15 mL/min/nmol). Both drugs stimulated CYP3A-mediated midazolam disappearance and 1-hydroxymidazolam formation in liver and intestinal microsomes.Conclusions: Gefitinib is more susceptible to CYP3A-mediated metabolism than erlotinib, which may contribute to the higher apparent oral clearance observed for gefitinib. Metabolism by hepatic and extrahepatic CYP1A may represent a determinant of pharmacokinetic variability and response for both drugs. The differential metabolizing enzyme profiles suggest that there may be differences in drug-drug interaction potential and that stimulation of CYP3A4 may likely play a role in drug interactions for erlotinib and gefitinib.
Hyperglycemia-Induced Thioredoxin-Interacting Protein Expression Differs in Breast Cancer–Derived Cells and Regulates Paclitaxel IC50
Authors: Turturro Francesco , Von Burton Gary , Friday Ellen 
Published: June 2007

Abstract
Purpose: We studied the hyperglycemia-induced expression of thioredoxin-interacting protein (TXNIP) expression and its relevance on the cytotoxic activity of paclitaxel in mammary epithelial–derived cell lines.
Experimental Design: Nontumorigenic cells (MCF10A); tumorigenic, nonmetastatic cells (MCF-7/T47D); and tumorigenic, metastatic cells (MDA-MB-231/MDA-MB-435s) were grown either in 5 or 20 mmol/L glucose chronically. Semiquantitative reverse transcription-PCR was used to assess TXNIP RNA expression in response to glucose. Reactive oxygen species were detected by CM-H2DCFDA (5-6-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate) and measured for mean fluorescence intensity with flow cytometry. Thioredoxin activity was assayed by the insulin disulfide-reducing assay. Proliferation was evaluated using CellTiter96 reagent with 490-nm absorption. Obtained absorbance values were used to calculate the paclitaxel IC50 in 5 or 20 mmol/L glucose using the Chou's dose-effect equation.
Results: We show that hyperglycemia by itself affects the level of TXNIP RNA in breast cancer–derived cells. TXNIP RNA level differs between nontumorigenic/nonmetastatic, tumorigenic cells (low TXNIP level), and metastatic cells (high TXNIP level). The differences in TXNIP RNA level, in reactive oxygen species level, and in thioredoxin activity are all related. We further show that hyperglycemia is a favorable condition in increasing the paclitaxel cytotoxicity by causing IC50 3-fold decrease in metastatic breast cancer–derived MDA-MB-231 cells. The increased paclitaxel cytotoxicity is associated with an additive effect on the hyperglycemia-mediated TXNIP expression more evident in conditions of hyperglycemia than normoglycemia.
Conclusions: Our study opens a new perspective on the relevance of metabolic conditions of hyperglycemia in the biology and treatment of cancer, particularly in view of the epidemic of diabetes.