bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mining the Tumor Phosphoproteome for Cancer Markers
Authors: Lim Yoon Pin 
Published: September 2005

Abstract
Despite decades of cancer research, mortality rates remain high largely due to the failure of early detection, poor understanding of the epidemiology of rational drug targets, and molecular etiology of human cancers. The discovery of disease markers promises to deliver some solutions to these formidable challenges. Gene and protein expression profiling through DNA microarray and proteomics have already made a tremendous effect in this area. However, protein/gene expression does not necessarily reflect protein activity, which is often regulated via post-translation modifications, of which phosphorylation is one of the most prominent. This is an important consideration because the activity of protein is a more relevant phenotype than its expression during pathogenesis. Tyrosine kinases represent a very important class of enzymes that are critical regulators of mitogenic and angiogenic signaling, hence attractive targets for anticancer drugs as exemplified by BCR-ABL and ErbB2. More than 50% of them are overexpressed or mutated resulting in a gain of function in various human cancers. In this review, we discuss the potential effect of phosphoproteins as cancer markers in cancer diagnosis and therapeutics. Phosphoproteomics strategies that might pave the way to high-throughput analysis for routine clinical applications are also described.
Green Tea Component, Catechin, Induces Apoptosis of Human Malignant B Cells via Production of Reactive Oxygen Species
Authors: Nakazato Tomonori , Ito Keisuke , Ikeda Yasuo , Kizaki Masahiro 
Published: September 2005

Abstract
Purpose: Green tea polyphenol, (−)-epigallocatechin-3-gallate, has been shown to inhibit cellular proliferation and induce apoptosis of various cancer cells. The aim of this study was to investigate the possibility of (−)-epigallocatechin-3-gallate as a novel therapeutic agent for the patients with B-cell malignancies including multiple myeloma.
Experimental Design: We investigated the effects of (−)-epigallocatechin-3-gallate on the induction of apoptosis in HS-sultan as well as myeloma cells in vitro and further examined the molecular mechanisms of (−)-epigallocatechin-3-gallate-induced apoptosis.
Results: (−)-Epigallocatechin-3-gallate rapidly induced apoptotic cell death in various malignant B-cell lines in a dose- and time-dependent manner. (−)-Epigallocatechin-3-gallate-induced apoptosis was in association with the loss of mitochondrial transmembrane potentials (Δψm); the release of cytochrome c, Smac/DIABLO, and AIF from mitochondria into the cytosol; and the activation of caspase-3 and caspase-9. Elevation of intracellular reactive oxygen species (ROS) production was also shown during (−)-epigallocatechin-3-gallate-induced apoptosis of HS-sultan and RPMI8226 cells as well as fresh myeloma cells. Antioxidant, catalase, and Mn superoxide dismutase significantly reduced ROS production and (−)-epigallocatechin-3-gallate-induced apoptosis, suggesting that ROS plays a key role in (−)-epigallocatechin-3-gallate-induced apoptosis in B cells. Furthermore, a combination with arsenic trioxide (As2O3) and (−)-epigallocatechin-3-gallate significantly enhanced induction of apoptosis compared with As2O3 alone via decreased intracellular reduced glutathione levels and increased production of ROS.
Conclusions: (−)-Epigallocatechin-3-gallate has potential as a novel therapeutic agent for patients with B-cell malignancies including multiple myeloma via induction of apoptosis mediated by modification of the redox system. In addition, (−)-epigallocatechin-3-gallate enhanced As2O3-induced apoptosis in human multiple myeloma cells.
Treatment of Relapsed Chronic Lymphocytic Leukemia by 72-Hour Continuous Infusion or 1-Hour Bolus Infusion of Flavopiridol: Results from Cancer and Leukemia Group B Study 19805
Authors: Byrd John C. , Peterson Bercedis L. , Gabrilove Janice , Odenike Olatoyosi M. , Grever Michael R. , Rai Kanti , Larson Richard A. ,   the Cancer and Leukemia Group B
Published: September 2005

Abstract
Purpose: Flavopiridol has in vitro activity in chronic lymphocytic leukemia (CLL) and promotes apoptosis independent of p53 function or prior fludarabine exposure. We sought to determine if flavopiridol has activity in previously treated CLL using two schedules of administration.
Patients and Methods: Patients with previously treated CLL were enrolled in two sequentially done phase II studies. Patients in the first trial received flavopiridol (50 mg/m2/d) as a continuous infusion (CI) for 72 hours every 2 weeks. Patients in the second trial received flavopiridol 50 mg/m2 as a 1-hour bolus (IVB) daily for 3 days repeated every 3 weeks. Patients received up to 12 (CI cohort) or 8 (IVB cohort) cycles of therapy.
Results: Fifteen patients were enrolled in the 72-hour CI phase II trial; 6 (40%) had intermediate-risk (Rai stage I or II) and 9 (60%) had high-risk (Rai stage III and IV) stages. No responses were noted in this group; 27% had stable disease and 73% had progressive disease. Thirty-six patients were enrolled in the second IVB trial, with 13 (36%) having intermediate and 23 (64%) having high-risk disease. Four patients (11%) had partial responses, 19 (53%) had stable disease, and 13 (36%) had progressive disease. The progression-free survival for responders in the IVB trial was 3, 3, 9, and 19 months. The median progression-free survival was 2 months [95% confidence interval (95% CI), 1.8-3.8] for patients in the CI trial and 3 months (95% CI, 2.5-7.4) for the IVB trial. The median overall survival was 27 months (95% CI, 20-42) for the CI trial and 24 months (95% CI, 18-31) for the IVB trial. Toxicity was manageable and included mainly myelosuppression, infections, diarrhea, and fatigue.
Conclusions: Flavopiridol has modest, schedule-dependent clinical activity in relapsed CLL and warrants future investigation utilizing alternative schedules of administration.
Comparative Preclinical and Clinical Pharmacokinetics of a Cremophor-Free, Nanoparticle Albumin-Bound Paclitaxel (ABI-007) and Paclitaxel Formulated in Cremophor (Taxol)
Authors: Sparreboom Alex , Scripture Charity D. , Trieu Vuong , Williams Paul J. , De Tapas , Yang Andrew , Beals Bridget , Figg William D. , Hawkins Michael , Desai Neil 
Published: September 2005

Abstract
Purpose: To compare the preclinical and clinical pharmacokinetic properties of paclitaxel formulated as a Cremophor-free, albumin-bound nanoparticle (ABI-007) and formulated in Cremophor-ethanol (Taxol).
Experimental Design: ABI-007 and Taxol were given i.v. to Harlan Sprague-Dawley male rats to determine pharmacokinetic and drug disposition. Paclitaxel pharmacokinetic properties also were assessed in 27 patients with advanced solid tumors who were randomly assigned to treatment with ABI-007 (260 mg/m2, 30 minutes; n = 14) or Taxol (175 mg/m2, 3 hours; n = 13), with cycles repeated every 3 weeks.
Results: The volume of distribution at steady state and clearance for paclitaxel formulated as Cremophor-free nanoparticle ABI-007 were significantly greater than those for paclitaxel formulated with Cremophor (Taxol) in rats. Fecal excretion was the main elimination pathway with both formulations. Consistent with the preclinical data, paclitaxel clearance and volume of distribution were significantly higher for ABI-007 than for Taxol in humans [21.13 versus 14.76 L/h/m2 (P = 0.048) and 663.8 versus 433.4 L/m2 (P = 0.040), respectively].
Conclusions: Paclitaxel formulated as ABI-007 differs from paclitaxel formulated as Taxol, with a higher plasma clearance and a larger volume of distribution. This finding is consistent with the absence of paclitaxel-sequestering Cremophor micelles after administration of ABI-007. This unique property of ABI-007 could be important for its therapeutic effectiveness.
Humoral Immune Response to Mesothelin in Mesothelioma and Ovarian Cancer Patients
Authors: Ho Mitchell , Hassan Raffit , Zhang Jingli , Wang Qing-cheng , Onda Masanori , Bera Tapan , Pastan Ira 
Published: September 2005

Abstract
Purpose: Mesothelin is a glycosyl-phosphatidylinositol–anchored glycoprotein present on the cell surface. Mesothelin is a differentiation antigen that is highly expressed on mesothelioma, ovarian cancer, and pancreatic cancer. The existence of a spontaneous humoral immune response to mesothelin in humans has not been fully studied. Here we addressed the issue of whether mesothelin elicits a humoral immune response in patients with mesothelioma and ovarian cancer.
Experimental Design: Using an ELISA, we analyzed immunoglobulin G antibodies specific for mesothelin in sera from patients with mesothelioma and epithelial ovarian cancer. Tumor specimens were examined by immunohistochemistry for mesothelin protein expression.
Results: Elevated levels of mesothelin-specific antibodies were detected in the sera of 39.1% of patients with mesothelioma (27 of 69 patients) and 41.7% with epithelial ovarian cancer (10 of 24 patients) when compared with a normal control population (44 blood donors; P &lt; 0.01 for both mesothelioma and ovarian cancer). We also found that 53% to 56% of patients with mesothelin immunostaining-positive mesothelioma and ovarian cancer had antibodies specific for mesothelin, whereas only 0% to 8% of patients with negative mesothelin immunostaining had detectable mesothelin-specific antibodies (χ2 test: P &lt; 0.01 for mesothelioma and P = 0.025 for ovarian cancer).
Conclusions: Our findings indicate that mesothelin is a new tumor antigen in patients with mesothelioma and ovarian cancer and the immunogenicity of mesothelin is associated with its high expression on the tumor cells. Mesothelin represents an excellent target for immune-based therapies.
Phase I Trial of 131I-huA33 in Patients with Advanced Colorectal Carcinoma
Authors: Chong Geoffrey , Lee Fook Thean , Hopkins Wendie , Tebbutt Niall , Cebon Jonathan S. , Mountain Angela J. , Chappell Bridget , Papenfuss Anthony , Schleyer Paul , U Paul , Murphy Roger , Wirth Veronika , Smyth Fiona E. , Potasz Nicole , Poon Aurora , Davis Ian D. , Saunder Tim , O'Keefe Graeme J. , Burgess Antony W. , Hoffman Eric W. , Old Lloyd J. , Scott Andrew M. 
Published: September 2005

Abstract
Purpose: Humanized monoclonal antibody A33 (huA33) targets the A33 antigen which is expressed on 95% of colorectal cancers. A previous study has shown excellent tumor-targeting of iodine-131 labeled huA33 (131I-huA33). Therefore, we did a phase I dose escalation trial of 131I-huA33 radioimmunotherapy.
Experimental Designs: Fifteen patients with pretreated metastatic colorectal carcinoma each received two i.v. doses of 131I-huA33. The first was an outpatient trace-labeled “scout” dose for biodistribution assessment, followed by a second “therapy” dose. Three patients were treated at 20, 30, and 40 mCi/m2 dose levels, and six patients at 50 mCi/m2 to define the maximum tolerated dose.
Results: Hematologic toxicity was 131I dose-dependent, with one episode of grade 4 neutropenia and two episodes of grade 3 thrombocytopenia observed at 50 mCi/m2. The maximum tolerated dose was determined to be 40 mCi/m2. There were no acute infusion-related adverse events, and gastrointestinal toxicity was not observed despite uptake of 131I-huA33 in bowel. Seven patients developed pruritus or rash, which was not related to 131I dose. There was excellent tumor-targeting of 131I-huA33 shown in all patients. The serum T1/2β of 131I-huA33 was (mean ± SD) 135.2 ± 46.9 hours. The mean absorbed tumor dose was 6.49 ± 2.47 Gy/GBq. Four patients developed human anti-human antibodies. At restaging, 4 patients had stable disease, whereas 11 patients had progressive disease.
Conclusion: Radioimmunotherapy using 131I-huA33 shows promise in targeting colorectal tumors, and is deliverable at a maximum tolerated dose of 40 mCi/m2. Further studies of 131I-huA33 in combination with chemotherapy are planned.
Methylation Profiling of Archived Non–Small Cell Lung Cancer: A Promising Prognostic System
Authors: Safar A. Mazin , Spencer Horace , Su Xiaobo , Coffey Maureen , Cooney Craig A. , Ratnasinghe Luke D. , Hutchins Laura F. , Fan Chun-Yang 
Published: September 2005

Abstract
Purpose: Enhanced prognostication power is becoming more desirable in clinical oncology. In this study, we explored the prognostic potential of multigene hypermethylation profiling in non–small-cell lung cancer.
Experimental Design: We evaluated a panel of eight genes (p16, APC, ATM, hMLH1, MGMT, DAPK, ECAD, and RASSF1A) using methylation-specific PCR in 105 archived specimens of non–small-cell lung cancer representing all stages of the illness. We analyzed the effect of gene methylation status on outcome individually in a cumulative manner and in a combinatorial approach using recursive partitioning to identify methylation profiles, which affect overall survival.
Results: In this data set, tumors harboring promoter hypermethylation at two or more genes exhibit similar survival trends to others in the cohort. Using recursive partitioning, three genes (APC, ATM, and RASSF1A) emerged as determinants of prognostic groups. This designation retained its statistical significance even when disease stage and age were entered into a multivariate analysis. Using this approach, patients whose tumors were hypermethylated at APC and those hypermethylated at only ATM (not also at APC or RASSF1A) enjoyed substantially longer 1- and 2-year survival than patients in the remaining groups. In 32 adjacent histologically normal lung tissue specimens, we detected similar methylation abnormalities.
Conclusion: Assessment of promoter hypermethylation aberrations may facilitate prognostic profiling of lung tumors, but validation in independent data sets is needed to verify these profiles. This system uses material that is abundantly available with linked outcome data and can be used to generate reliable epigenetic determinants.
P53 Mutation Analysis of Colorectal Liver Metastases: Relation to Actual Survival, Angiogenic Status, and p53 Overexpression
Authors: de Jong Koert P. , Gouw Annette S.H. , Peeters Paul M.J.G. , Bulthuis Marian , Menkema Lorian , Porte Robert J. , Slooff Maarten J.H. , van Goor Harry , van den Berg Anke 
Published: September 2005

Abstract
Purpose: To correlate TP53 mutations with angiogenic status of the tumor and prognosis after liver surgery in patients with colorectal liver metastases and to correlate immunohistochemical staining of p53 protein with TP53 gene mutations.
Experimental Design: Tumors of 44 patients with surgically treated colorectal liver metastases were analyzed for (a) TP53 mutations using denaturing gradient gel electrophoresis followed by sequencing, (b) microvessel density using the hot spot overlap technique, (c) apoptotic rate in tumor cells and endothelial cells of tumor microvessels using double immunostaining for anti–cleaved caspase 3 and anti-CD34, and (d) expression of p53 protein using immunohistochemistry.
Results:TP53 mutations were detected in 36% of the metastases and occurred more frequently in liver metastases from left-sided colon tumors than from right-sided colon tumors (P = 0.04). In metastases with TP53 mutations, microvessel density was higher compared with tumors with wild-type p53. Endothelial cell apoptosis was not different in tumor microvessels from TP53-mutated versus nonmutated tumors. The 5-year actual survival was not influenced by TP53 mutational status, microvessel density, or endothelial cell apoptotic rate of the tumors. Based on immunohistochemical p53 overexpression, the positive and negative predictive values of TP53 mutations were 61% and 82%.
Conclusions: In patients with surgically treated colorectal liver metastases, TP53 mutations and angiogenic status did not influence prognosis. Immunohistochemistry is not a reliable technique for detecting TP53 mutations.
Dual Inhibition of mTOR and Estrogen Receptor SignalingIn vitroInduces Cell Death in Models of Breast Cancer
Authors: Boulay Anne , Rudloff Joelle , Ye Jingjing , Zumstein-Mecker Sabine , O'Reilly Terence , Evans Dean B. , Chen Shiuan , Lane Heidi A. 
Published: September 2005

AbstractPurpose: RAD001 (everolimus), a mammalian target of rapamycin (mTOR) pathway inhibitor in phase II clinical trials in oncology, exerts potent antiproliferative/antitumor activities. Many breast cancers are dependent for proliferation on estrogens synthesized from androgens (i.e., androstenedione) by aromatase. Letrozole (Femara) is an aromatase inhibitor used for treatment of postmenopausal women with hormone-dependent breast cancers. The role of the mTOR pathway in estrogen-driven proliferation and effects of combining RAD001 and letrozole were examined in vitro in two breast cancer models.Experimental Design: The role of the mTOR pathway in estrogen response was evaluated in aromatase-expressing MCF7/Aro breast cancer cells by immunoblotting. Effects of RAD001 and letrozole (alone and in combination) on the proliferation and survival of MCF7/Aro and T47D/Aro cells were evaluated using proliferation assays, flow cytometry, immunoblotting, and apoptosis analyses.Results: Treatment of MCF7/Aro cells with estradiol or androstenedione caused modulation of the mTOR pathway, a phenomenon reversed by letrozole or RAD001. In MCF7/Aro and T47D/Aro cells, both agents inhibited androstenedione-induced proliferation; however, in combination, this was significantly augmented (P &lt; 0.001, two-way ANOVA, synergy by isobologram analysis). Increased activity of the combination correlated with more profound effects on G1 progression and a significant decrease in cell viability (P &lt; 0.01, two-way ANOVA) defined as apoptosis (P &lt; 0.05, Friedman test). Increased cell death was particularly evident with optimal drug concentrations.Conclusion: mTOR signaling is required for estrogen-induced breast tumor cell proliferation. Moreover, RAD001-letrozole combinations can act in a synergistic manner to inhibit proliferation and trigger apoptotic cell death. This combination holds promise for the treatment of hormone-dependent breast cancers.
Prediction of BRCA1 Status in Patients with Breast Cancer Using Estrogen Receptor and Basal Phenotype
Authors: Lakhani Sunil R. , Reis-Filho Jorge S. , Fulford Laura , Penault-Llorca Frederique , van der Vijver Marc , Parry Suzanne , Bishop Timothy , Benitez Javier , Rivas Carmen , Bignon Yves-Jean , Chang-Claude Jenny , Hamann Ute , Cornelisse Cees J. , Devilee Peter , Beckmann Matthias W. , Nestle-Krämling Carolin , Daly Peter A. , Haites Neva , Varley Jenny , Lalloo Fiona , Evans Gareth , Maugard Christine , Meijers-Heijboer Hanne , Klijn Jan G.M. , Olah Edith , Gusterson Barry A. , Pilotti Silvana , Radice Paolo , Scherneck Siegfried , Sobol Hagay , Jacquemier Jocelyne , Wagner Teresa , Peto Julian , Stratton Michael R. , McGuffog Lesley , Easton Douglas F. ,   the Breast Cancer Linkage Consortium
Published: September 2005

Abstract
Purpose: To investigate the proportion of breast cancers arising in patients with germ line BRCA1 and BRCA2 mutations expressing basal markers and developing predictive tests for identification of high-risk patients.
Experimental Design: Histopathologic material from 182 tumors in BRCA1 mutation carriers, 63 BRCA2 carriers, and 109 controls, collected as part of the international Breast Cancer Linkage Consortium were immunohistochemically stained for CK14, CK5/6, CK17, epidermal growth factor receptor (EGFR), and osteonectin.
Results: All five basal markers were commoner in BRCA1 tumors than in control tumors (CK14: 61% versus 12%; CK5/6: 58% versus 7%; CK17: 53% versus 10%; osteonectin: 43% versus 19%; EGFR: 67% versus 21%; P &lt; 0.0001 in each case). In a multivariate analysis, CK14, CK5/6, and estrogen receptor (ER) remained significant predictors of BRCA1 carrier status. In contrast, the frequency of basal markers in BRCA2 tumors did not differ significant from controls.
Conclusion: The use of cytokeratin staining in combination with ER and morphology provides a more accurate predictor of BRCA1 mutation status than previously available, that may be useful in selecting patients for BRCA1 mutation testing. The high percentage of BRCA1 cases positive for EGFR suggests that specific anti-tyrosine kinase therapy may be of potential benefit in these patients.
Enhanced Pharmacodynamic and Antitumor Properties of a Histone Deacetylase Inhibitor Encapsulated in Liposomes or ErbB2-Targeted Immunoliposomes
Authors: Drummond Daryl C. , Marx Corina , Guo Zexiong , Scott Gary , Noble Charles , Wang Donghui , Pallavicini Maria , Park John W. , Kirpotin Dmitri B. , Benz Christopher C. 
Published: September 2005

Abstract
ErbB2-overexpressing human cancers represent potentially sensitive targets for therapy by candidate histone deacetylase (HDAC) inhibitors as we have shown that HDAC inhibitors can selectively reduce ErbB2 expression by repressing the ErbB2 promoter and accelerating the decay of cytoplasmic ErbB2 transcripts. To extend these in vitro findings and enhance the in vivo pharmacodynamic properties of HDAC inhibitors, we stably encapsulated a potent hydroxamate-based HDAC inhibitor (LAQ824) within long-circulating liposomes (Ls-LAQ824) and immunoliposomes (ILs-LAQ824) bearing &gt;10,000 LAQ824 molecules per nanovesicle. Liposomal LAQ824 exhibits prolonged in vivo stability and, unlike free LAQ824, circulates with a half-life of 10.8 hours following a single i.v. injection. Three weekly i.v. injections of 20 to 25 mg/kg Ls-LAQ824 in nude mice with ErbB2 overexpressing BT-474 breast tumor xenografts significantly impairs tumor growth, and administration of ErbB2-targeted ILs-LAQ824 may further improve this antitumor activity. Studies of tumor-bearing mice 24 hours after single treatment indicate that: (a) &gt;10% of injected liposomal LAQ824 is still circulating (whereas free LAQ824 is undetectable in the blood after 15 minutes); and (b) tumor uptake of Ls-LAQ824 and ILs-LAQ824 is &gt;3% injected drug per gram of tumor, producing levels of acetylated tumor histones that are 5- to 10-fold increased over those following free LAQ824 or saline treatments and resulting in concordantly reduced levels of tumor ErbB2 mRNA. These preclinical results support the clinical evaluation of HDAC inhibitors against ErbB2-overexpressing malignancies, and further indicate that encapsulation into targeted and nontargeted liposomes substantially improves the in vivo pharmacokinetics, tumor uptake, and antitumor properties of hydroxamate-based HDAC inhibitors.
Trastuzumab-Mediated Antibody-Dependent Cellular Cytotoxicity against Esophageal Squamous Cell Carcinoma
Authors: Mimura Kousaku , Kono Koji , Hanawa Mitsuhiko , Kanzaki Mirei , Nakao Atsuhito , Ooi Akishi , Fujii Hideki 
Published: September 2005

Abstract
Purpose: In the present study, we investigated the degree of protein expression and gene amplification of HER-2 in esophageal squamous cell carcinoma (SCC) cell lines and freshly isolated tumors, and trastuzumab-mediated biological activity, in particular antibody-dependent cellular cytotoxicity (ADCC) against HER-2–expressing esophageal SCC cell lines.
Experimental Design: Ten different SCC cell lines with various levels of HER-2 status evaluated by flow cytometry, immunocytochemistry (HercepTest), and fluorescence in situ hybridization were evaluated for ADCC, growth inhibitory, or apoptosis-inducing activities mediated by trastuzumab.
Results: Trastuzumab induced ADCC against HER-2–expressing esophageal SCC and the activities reflected the degree of HER-2 expression analyzed by flow cytometric analysis, but not by HercepTest nor fluorescence in situ hybridization analysis. Furthermore, trastuzumab-mediated ADCC against transforming growth factor-β–producing SCC was enhanced by the treatment with SB-431542, which is a selective inhibitor of the phosphorylation induced by transforming growth factor-β. There were very marginal effects of anti-proliferative or apoptosis-inducing activities mediated by trastuzumab for HER-2–expressing esophageal SCC.
Conclusion: HER-2–expressing esophageal SCC cells could be killed by trastuzumab-mediated ADCC and the activity reflected the degree of HER-2 expression detected by flow cytometry.