bluuebunny/crossref_metadata_2025_split huggingface dataset:
Farnesyltransferase Inhibitors and Human Malignant Pleural Mesothelioma: A First-Step Comparative Translational Study
Authors: Cesario Alfredo , Catassi Alessia , Festi Luigi , Imperatori Andrea , Pericelli Andrea , Galetta Domenico , Margaritora Stefano , Porziella Venanzio , Cardaci Vittorio , Granone Pierluigi , Dominioni Lorenzo , Russo Patrizia 
Published: September 2005

Abstract
It is known that the potential clinical use of farnesyltransferase inhibitors (FTI) could be expanded to include cancers harboring activated receptor tyrosine kinases. Approximately 70% of malignant pleural mesotheliomas (MPM) overexpress epidermal growth factor receptors (EGFR) and a subset express both EGFR and transforming growth factor α (TGF-α), suggesting an autocrine role for EGFR in MPM. We checked on MPM cells (10 human cell lines, 11 primary cultures obtained by human biopsies, and 7 short-term normal mesothelial cell cultures) concerning the following: (a) the relative overexpression of EGFR (Western blotting, flow cytometry, immunohistochemistry), (b) the relative expression of EGFR ligands (EGF, amphiregulin, TGF-α, ELISA), (c) the relative increase of the activated form of Ras (Ras-bound GTP) after EGF stimulation (Ras activation assay), (d) the efficacy of five different FTIs (HDJ2 prenylation, cell cytotoxicity, and apoptosis using ApopTag and gel ladder). EGFR was overexpressed in MPM cells compared with normal pleural mesothelial cells in equivalent levels as in non–small cell lung cancer cells A459. MPM cells constitutively expressed EGFR ligands; however, Ras activation was attenuated at high EGF concentrations (100 ng/mL). Growth of MPM cells was substantially not affected by treatment with different FTIs (SCH66336, BMS-214662, R115777, RPR-115135, and Manumycin). Among these, BMS-214662 was the only one moderately active. BMS-214662 triggered apoptosis in a small fraction of cells (not higher than 30%) that was paralleled by a slight decrease in the levels of TGF-α secreted by treated MPM cells. Our data highlighted the concept that the same signaling pathway can be regulated in different ways and these regulations can differ between different cells of different origin.
Phase I Clinical and Pharmacokinetic Study of Kahalalide F in Patients with Advanced Androgen Refractory Prostate Cancer
Authors: Rademaker-Lakhai Jeany M. , Horenblas Simon , Meinhardt Willem , Stokvis Ellen , de Reijke Theo M. , Jimeno José M. , Lopez-Lazaro Luis , Lopez Martin José A. , Beijnen Jos H. , Schellens Jan H.M. 
Published: September 2005

Abstract
Purpose: The purpose is to determine the maximum tolerated dose, profile of adverse events, and dose-limiting toxicity of Kahalalide F (KF) in patients with androgen refractory prostate cancer. Furthermore, the pharmacokinetics after KF administration and preliminary antitumor activity were evaluated. KF is a dehydroaminobutyric acid–containing peptide isolated from the marine herbivorous mollusk, Elysia rufescens.
Experimental Design: Adult patients with advanced or metastatic androgen refractory prostate cancer received KF as an i.v. infusion over 1 hour, during five consecutive days every 3 weeks. The starting dose was 20 μg per m2 per day. Clinical pharmacokinetics studies were done in all patients using noncompartmental analysis. Prostate-specific antigen levels were evaluated as a surrogate marker for activity against prostate cancer.
Results: Thirty-two patients were treated at nine dose levels (20-930 μg per m2 per day). The maximum tolerated dose on this schedule was 930 μg per m2 per day. The dose-limiting toxicity was reversible and asymptomatic Common Toxicity Criteria grade 3 and 4 increases in transaminases. The recommended dose for phase II studies is 560 μg per m2 per day. Pharmacokinetics analysis revealed dose linearity up to the recommended dose. Thereafter, a more than proportional increase was observed. Elimination was rapid with a mean (SD) terminal half-life (t1/2) of 0.47 hour (0.11 hour). One patient at dose level 80 μg per m2 per day had a partial response with a prostate-specific antigen decline by at least 50% for ≥4 weeks. Five patients showed stable disease.
Conclusions: KF can be given safely as a 1-hour i.v. infusion during five consecutive days at a dose of 560 μg per m2 per day once every 3 weeks.
Caspase-Dependent Apoptosis Induction by Phenethyl Isothiocyanate, a Cruciferous Vegetable-Derived Cancer Chemopreventive Agent, Is Mediated by Bak and Bax
Authors: Xiao Dong , Zeng Yan , Choi Sunga , Lew Karen L. , Nelson Joel B. , Singh Shivendra V. 
Published: September 2005

Abstract
Purpose: The present study was undertaken to gain insights into the molecular mechanism of apoptosis induction by phenethyl isothiocyanate (PEITC) using prostate cancer cell lines derived from transgenic adenocarcinoma mouse prostate (TRAMP) mice (TRAMP-C1 and TRAMP-C2).
Experimental Design and Results: The viability of TRAMP-C1 and TRAMP-C2 cells was reduced significantly in the presence of PEITC in a concentration-dependent manner as determined by sulforhodamine B and trypan blue dye exclusion assays. Treatment of TRAMP-derived cells with PEITC revealed features characteristic of apoptosis induction, including appearance of subdiploid cells (determined by flow cytometry), cytoplasmic histone-associated DNA fragmentation (determined by an ELISA assay), and cleavage of caspase-3 (determined by immunoblotting). The PEITC-induced apoptosis in TRAMP-derived cells was associated with a marked increase in the level of proapoptotic protein Bak and/or a decrease in the levels of antiapoptotic protein Mcl-1 or Bcl-xL and disruption of mitochondrial membrane potential. The SV40 immortalized mouse embryonic fibroblasts derived from Bak and Bax double knockout mice were significantly more resistant to PEITC-induced DNA fragmentation compared with wild-type or Bak−/− mouse embryonic fibroblasts. The PEITC-induced apoptosis in both cell lines was significantly attenuated in the presence of caspase inhibitors zVAD-fmk, zLEHD-fmk, and zIETD-fmk. Oral administration of PEITC (9 or 12 μmol PEITC/d, Monday-Friday) significantly retarded growth of TRAMP-C1 xenografts in nude mice without causing weight loss or any other side effects.
Conclusion: The results of the present study indicate that caspase-dependent apoptosis by PEITC is mediated by Bak and Bax proteins.
Risk Assessment in Patients with Acute Myeloid Leukemia and a Normal Karyotype
Authors: Bienz Marianne , Ludwig Madleina , Mueller Beatrice U. , Oppliger Leibundgut Elisabeth , Ratschiller Daniel , Solenthaler Max , Fey Martin F. , Pabst Thomas 
Published: September 2005

Abstract
Purpose: The recognition of a number of leukemia-specific cytogenetic abnormalities and their role as independent prognostic factors have provided considerable insights into leukemia pathogenesis and have paved the way to adopt risk-adapted treatment. However, ∼50% of newly diagnosed acute myeloid leukemia (AML) have a normal karyotype. There has therefore been much interest in identifying molecular markers that could help to improve the prognostic stratification of patients with normal-karyotype AML.
Experimental Design: Consecutive untreated AML patients (n = 67) from a single institution all with normal karyotype were analyzed for the presence of mutations in the myeloid transcription factor gene CEBPA (for CCAAT/enhancer binding protein-α), for internal tandem duplications (ITD) of the tyrosine kinase receptor gene FLT3 (for fms-like tyrosine kinase 3), and for expression of the BAALC gene (for brain and acute leukemia, cytoplasmic).
Results: 17.9% of normal-karyotype AML had mutations in the CEBPA gene, and 28.4% had FLT3-ITD; 65.7% (44 of 67) had high BAALC expression and 34.3% (23 of 67) had low BAALC expression. Patients with CEBPA mutations had a very favorable course of their disease. Median disease-free survival (DFS) and overall survival (OS) were 33.5 and 45.5 months, respectively, compared with 10 (e.g., 12 months in patients without CEBPA mutations; P = 0.0017; P = 0.0007). AML patients with FLT3-ITD had significantly shorter median DFS (P = 0.0328) and OS (P = 0.0148) than patients without FLT3-ITD. High BAALC expression predicted for a shorter DFS (P = 0.0152) and OS (P = 0.0210) compared with AML with low BAALC expression; 53.7% of normal-karyotype AML had neither FLT3-ITD nor CEBPA mutations. We found that high BAALC expression in normal-karyotype AML with neither FLT3-ITD nor CEBPA mutations (18 of 67) indicates adverse prognosis for both DFS and OS (P = 0.0001; e.g., P = 0.0001) compared with the group with low BAALC expression and absent FLT3-ITD and CEBPA mutations (18 of 67). Thus, BAALC expression represents a novel prognostic marker particularly for normal-karyotype AML patients with neither FLT3-ITD nor CEBPA mutations.
Conclusions: Assessment of CEBPA mutations, FLT3-ITD, and BAALC expression permits to split normal-karyotype AML into clinically distinct subgroups.
Myc Down-Regulation Sensitizes Melanoma Cells to Radiotherapy by Inhibiting MLH1 and MSH2 Mismatch Repair Proteins
Authors: Bucci Barbara , D'Agnano Igea , Amendola Donatella , Citti Arianna , Raza Giorgio H. , Miceli Roberto , De Paula Ugo , Marchese Rodolfo , Albini Sonia , Felsani Armando , Brunetti Ercole , Vecchione Aldo 
Published: September 2005

Abstract
Purpose: Melanoma patients have a very poor prognosis with a response rate of &lt;1% due to advanced diagnosis. This type of tumor is particularly resistant to conventional chemotherapy and radiotherapy, and the surgery remains the principal treatment for patients with localized melanoma. For this reason, there is particular interest in the melanoma biological therapy.
Experimental Design: Using two p53 mutant melanoma models stably expressing an inducible c-myc antisense RNA, we have investigated whether Myc protein down-regulation could render melanoma cells more susceptible to radiotherapy, reestablishing apoptotic p53-independent pathway. In addition to address the role of p53 in the activation of apoptosis, we studied the effect of Myc down-regulation on radiotherapy sensitivity also in a p53 wild-type melanoma cell line.
Results: Myc down-regulation is able per se to induce apoptosis in a fraction of the cell population (∼40% at 72 hours) and in combination with γ radiation efficiently enhances the death process. In fact, ∼80% of apoptotic cells are evident in Myc down-regulated cells exposed to γ radiation for 72 hours compared with ∼13% observed after only γ radiation treatment. Consistent with the enhanced apoptosis is the inhibition of the MLH1 and MSH2 mismatch repair proteins, which, preventing the correction of ionizing radiation mismatches occurring during DNA replication, renders the cells more prone to radiation-induced apoptosis.
Conclusions: Data herein reported show that Myc down-regulation lowers the apoptotic threshold in melanoma cells by inhibiting MLH1 and MSH2 proteins, thus increasing cell sensitivity to γ radiation in a p53-independent fashion. Our results indicate the basis for developing new antitumoral therapeutic strategy, improving the management of melanoma patients.
Combined GADD45A and Thymidine Phosphorylase Expression Levels Predict Response and Survival of Neoadjuvant-Treated Gastric Cancer Patients
Authors: Napieralski Rudolf , Ott Katja , Kremer Markus , Specht Katja , Vogelsang Holger , Becker Karen , Müller Martina , Lordick Florian , Fink Ulrich , Rüdiger Siewert Jörg , Höfler Heinz , Keller Gisela 
Published: September 2005

Abstract
Purpose: We evaluated the expression of seven therapy-related genes to predict the clinical outcome of advanced gastric cancer patients treated with a neoadjuvant chemotherapeutic protocol.
Experimental Design: Pretherapeutic, formalin-fixed, and paraffin-embedded biopsies of 61 patients, who received a 5-fluorouracil (5-FU)– and cisplatin-based chemotherapy were studied. The expressions of the 5-FU–related genes TS, DPD, and TP and of the cisplatin-related genes ERCC1, ERCC4, KU80, and GADD45A were analyzed by quantitative real-time PCR. The expression levels of single genes and of various combinations were tested for an association with response and overall survival.
Results: High DPD levels were more frequently found in nonresponding patients and were associated with worse survival. GADD45A and TP levels showed weak associations with response, but GADD45A expression correlated with survival. There was no association with response for TS expression, but tumors with a high TS level were associated with worse survival. The combination of GADD45A and TP revealed the strongest predictive effect. High expression values of TP and/or GADD45A were exclusively found in nonresponding patients (P = 0.002) and were associated with a significantly poorer survival (P = 0.04).
Conclusions: Combined gene expression levels of TP and GADD45A represent a new variable to predict the clinical outcome after neoadjuvant chemotherapy in gastric cancer. The association of DPD expression with response and survival underlines a predominant role of DPD to predict 5-FU sensitivity. The association of TS expression levels with survival but not with response suggests an importance of this gene for tumor progression.
The Clinical Significance of Aurora-A/STK15/BTAK Expression in Human Esophageal Squamous Cell Carcinoma
Authors: Tanaka Eiji , Hashimoto Yosuke , Ito Tetsuo , Okumura Tomoyuki , Kan Takatsugu , Watanabe Go , Imamura Masayuki , Inazawa Johji , Shimada Yutaka 
Published: September 2005

Abstract
Purpose: Aurora-A/STK15/BTAK (Aurora-A) encodes a Serine/Threonine kinase associated with chromosomal distribution, and its up-regulation induces chromosomal instability thereby leading to aneuploidy and cell transformation in several types of cancer. In this study, we investigated the role of Aurora-A in human esophageal squamous cell carcinoma (ESCC).
Experimental Design: The expression levels of Aurora-A mRNA were compared in 33 ESCC tissues with that in corresponding normal esophageal epithelium by semiquantitative reverse transcription-PCR, and the distribution patterns and expression levels of Aurora-A protein were immunohistochemically investigated in the ESCC tumors of 142 patients. The results were then separately compared with the clinicopathologic findings of the patients, and the expression of Aurora-A was examined in nine ESCC cell lines and a normal esophageal epithelial cell line using Western blot analysis.
Results: The up-regulation of Aurora-A mRNA was found in 30% (10 of 33) of the tumors by semiquantitative reverse transcription-PCR, and protein up-regulation was found in 53% (75 of 142) of the patients by immunohistochemistry. mRNA and protein up-regulation of Aurora-A were correlated with distant lymph node metastasis (P = 0.05 and P = 0.04, respectively), and patients with Aurora-A mRNA or protein up-regulation had a poorer prognosis (P = 0.003 and P = 0.0009, respectively). Furthermore, multivariate analysis revealed that up-regulation of the Aurora-A protein was an independent prognostic factor. In addition, Aurora-A expression in all ESCC cell lines was higher than that in a normal esophageal epithelial cell line.
Conclusions: The up-regulation of Aurora-A expression may reflect the malignant behavior of ESCC and may prove useful information as a prognostic factor for ESCC patients.
In vivo Radioiodide Imaging and Treatment of Breast Cancer Xenografts after MUC1-Driven Expression of the Sodium Iodide Symporter
Authors: Dwyer Roisin M. , Bergert Elizabeth R. , O'Connor Michael K. , Gendler Sandra J. , Morris John C. 
Published: September 2005

Abstract
Purpose: Expression of the sodium iodide symporter (NIS) in the thyroid gland provides for effective imaging and treatment of thyroid cancer using radiolabeled iodide. Transfer of NIS into other tumors would expand the utility of this treatment to tumors of nonthyroid origin. MUC1 is a transmembrane glycoprotein that is overexpressed in many tumor types, including breast, pancreatic, and ovarian. The aim of this study was to create a construct containing NIS under the control of the MUC1 promoter to target expression specifically to MUC1-positive breast cancer cells.
Experimental Design: A replication-deficient adenoviral construct was created containing the MUC1 promoter followed by the human NIS gene. Iodide uptake assays, Western blot, and immunohistochemistry were used to confirm NIS expression and function. Breast cancer xenografts in mice were infected with Ad5/MUC1/NIS and then imaged and treated using radioiodide.
Results: A 58-fold increase in iodide uptake was observed in infected MUC1-positive T47D cells with no significant increase observed in MUC1-negative MDA-MB-231 cells or in cells infected with the control virus. The in vivo study yielded clear images of Ad/MUC1/NIS-infected tumor xenografts using 123I. Administration of a therapeutic dose of 131I resulted in an 83% reduction in tumor volume, whereas control tumors continued to increase in size (P &lt; 0.01).
Conclusions: These results show that the MUC1 promoter is capable of directing efficient and selective expression of the NIS gene in MUC1-positive breast tumor cells. This could potentially have applications for both imaging and therapy in a range of MUC1-positive tumor types.
Phase I Study of the Farnesyltransferase Inhibitor BMS-214662 Given Weekly in Patients with Solid Tumors
Authors: Papadimitrakopoulou Vali , Agelaki Sofia , Tran Hai T. , Kies Merrill , Gagel Robert , Zinner Ralph , Kim Edward , Ayers Gregory , Wright John , Khuri Fadlo 
Published: September 2005

Abstract
Purpose: A phase I trial of BMS-214662, a selective farnesyltransferase inhibitor with significant preclinical antitumor activity in which drug was given as a weekly 1-hour infusion for four of six weeks, was conducted to evaluate the tolerability, pharmacokinetics, and pharmacodynamic effect on farnesyltransferase activity in peripheral blood mononuclear cells.
Experimental Design: BMS-214662 was given to 27 patients with solid tumors at 10 escalating dose levels (28-220 mg/m2) allowing intrapatient dose escalation; pharmacokinetics and pharmacodynamics were done at the first seven dose levels.
Results: Grade 4 neutropenia (four patients) was the most common dose-limiting toxicity followed by aminotransferase elevation (grade 3 alanine aminotransferase and grade 4 aspartate aminotransferase) and grade 3 dehydration. Most frequent toxicities were neutropenia in 11 (14%), anemia in 15 (19%), fatigue in 9 (12%), and nausea and diarrhea in 6 (8%) of courses, respectively. One minor response lasting 18 weeks in a patient with non–small cell lung cancer, serum calcitonin level reduction accompanied by disease stabilization in two of four patients with medullary thyroid carcinoma, and stable disease in 16 of 25 evaluable patients was seen. No correlation was observed between dose and Cmax, total body clearance (mean, 26.15 ± 10.88 L per hour per m2), volume of distribution at steady state (mean, 39.51 ± 17.91 L/m2), or half-life (mean, 2.63 ± 1.81 hours); a moderate correlation existed between dose given and systemic drug exposure (AUC). Substantial inhibition of peripheral blood mononuclear cell farnesyltransferase activity but near complete recovery by 24 hours was seen.
Conclusion: BMS-214667 was well tolerated as a weekly 1-hour i.v. infusion for four of six weeks with evidence of pharmacodynamic effect. The study was terminated before maximum tolerated dose was reached. Alternative schedules of drug administration might result in improved pharmacodynamic profile.
4-Hydroxytamoxifen Inhibits Proliferation of Multiple Myeloma Cells In vitro through Down-Regulation of c-Myc, Up-Regulation of p27Kip1, and Modulation of Bcl-2 Family Members
Authors: Gauduchon Juliette , Gouilleux Fabrice , Maillard Sébastien , Marsaud Véronique , Renoir Jack-Michel , Sola Brigitte 
Published: September 2005

Abstract
Purpose: Multiple myeloma is an incurable B-cell malignancy requiring new therapeutic strategies. Our approach was to analyze the in vitro effects of a selective estrogen receptor modulator, 4-hydroxytamoxifen (4-OHT), on six multiple myeloma cell lines.
Experimental Design: Cultured multiple myeloma cells were treated with various 4-OHT concentrations and the cellular response was studied: cell proliferation, cell viability, induction of apoptosis, caspase activities, and expression of signaling proteins.
Results: We found that pharmacologic concentrations of 4-OHT inhibit cell proliferation (4 of 6 cell lines). This inhibition is achieved by two independent events: a block at the G1 phase of the cell cycle and the induction of apoptotic death. The cellular response to 4-OHT depends on the presence of functional estrogen receptors. 4-OHT treatment activates an intrinsic mitochondrial caspase-9-dependent pathway but not the Fas/FasL death pathway. Signaling pathways known to be involved in the survival and/or proliferation of multiple myeloma cells are not affected by 4-OHT treatment. 4-OHT-induced G1 arrest is accompanied by the up-regulation of the cell cycle inhibitor p27Kip1 and the down-regulation of c-Myc. Among the Bcl-2 family members tested, the proapoptotic BimS protein is induced whereas the antiapoptotic protein Mcl-1 is decreased.
Conclusions: Although the effects of 4-OHT are observed at micromolar concentrations, cellular mechanisms responsible for G1 arrest, as well as apoptosis induction, are similar to those observed in breast cancer cells. Our data support the concept that 4-OHT may represent an alternative approach to inhibit proliferation and induce apoptosis of multiple myeloma cells.
Overexpression of 5-Lipoxygenase and Cyclooxygenase 2 in Hamster and Human Oral Cancer and Chemopreventive Effects of Zileuton and Celecoxib
Authors: Li Ning , Sood Sandeep , Wang Su , Fang Mingzhu , Wang Peng , Sun Zheng , Yang Chung S. , Chen Xiaoxin 
Published: September 2005

Abstract
Purpose: Previous studies have suggested an important role of aberrant arachidonic acid metabolism, especially the cyclooxygenase (Cox) pathway, in oral carcinogenesis. However, it is unknown whether the 5-lipoxygenase (5-Lox) pathway contributes to oral carcinogenesis, and whether combination of inhibitors of both pathways may have synergistic or additive effects of chemoprevention.
Experimental Design: 5-Lox expression was examined in 7,12-dimethylbenz[a]anthracene (DMBA)–induced hamster and human oral cancer tissues by immunohistochemistry, and Cox2 expression was investigated in hamster oral tissues using in situ hybridization. Zileuton (a specific 5-Lox inhibitor) and celecoxib (a specific Cox2 inhibitor), either alone or in combination, were investigated for their chemopreventive effects on the DMBA-induced hamster model at the post-initiation stage through topical application.
Results: 5-Lox was overexpressed during oral carcinogenesis in hamsters and humans, as well as Cox2 in the hamster tissues. In a chemoprevention study using the post-initiation DMBA model, incidence of hamster oral squamous cell carcinoma was reduced from 76.9% (20 of 26) to 45.8% (11 of 24, P &lt; 0.05) and 32.1% (9 of 28, P &lt; 0.01) by 3% and 6% topical zileuton, respectively; and to 57.6% (15 of 26, P &gt; 0.05) and 50% (12 of 24, P &lt; 0.05) by 3% and 6% topical celecoxib, respectively. When used in combination, celecoxib and zileuton (3% of each) had an additive inhibitory effect on the incidence of squamous cell carcinoma (36%, 9 of 25, P &lt; 0.01). Other pathologic variables and the levels of leukotriene B4 and prostaglandin E2 of the hamster tissues were reduced as well.
Conclusions: The results clearly showed that both 5-Lox and Cox2 played important roles in oral carcinogenesis. Zileuton and celecoxib prevented oral carcinogenesis at the post-initiation stage through their inhibitory effects on arachidonic acid metabolism.