bluuebunny/crossref_metadata_2025_split huggingface dataset:
ZD1839 Modulates Paclitaxel Response in Renal Cancer by Blocking Paclitaxel-Induced Activation of the Epidermal Growth Factor Receptor–Extracellular Signal-Regulated Kinase Pathway
Authors: Sumitomo Makoto , Asano Tomohiko , Asakuma Junichi , Asano Takako , Horiguchi Akio , Hayakawa Masamichi 
Published: September 2005

Abstract
Purpose: We evaluated the antitumor activity of ZD1839, a selective epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor, in combination with paclitaxel in human renal cell carcinomas (RCCs).
Experimental Design: Eight human RCC lines and the surgical specimens obtained from 10 RCC patients were used. The protein expression was detected by Western blotting, immunohistochemistry and/or flow cytometry. Apoptosis was evaluated by flow cytometry and fragmented DNA ELISA. SKRC-49 tumor xenografts in athymic nude mice were treated with ZD1839 and/or paclitaxel, and tumor volume was determined
Results: EGFR protein was expressed and phosphorylated in eight RCC lines and EGFR expression was markedly increased in RCC specimens compared with adjacent normal renal tissues. Treatment of SKRC-49 with 1 μm ZD1839 resulted in a marked decrease in the phosphorylation of EGFR but not of HER-2. Treatment of SKRC-49 with ZD1839 in combination with 5 nm paclitaxel resulted in a significant increase in apoptotic cell number compared with paclitaxel alone, whereas ZD1839 alone failed to induce apoptosis. Although administration of ZD1839 or paclitaxel resulted in a transient growth inhibition in SKRC-49 xenografts, significant tumor regrowth delay was observed when paclitaxel was combined with ZD1839. Paclitaxel phosphorylated extracellular signal-regulated kinase through EGFR activation predominantly in cancer cells. ZD1839 promoted paclitaxel-induced Bcl-2 down-regulation resulting in promoting apoptosis by blocking paclitaxel-induced activation of the EGFR—extracellular signal-regulated kinase antiapoptotic pathway independent of Akt activity in SKRC-49.
Conclusions: Our findings support the idea that the significant clinical benefit is obtained from ZD1839 in combination with paclitaxel for the treatment of RCC.
High-Throughput Analysis of Genome-Wide Receptor Tyrosine Kinase Expression in Human Cancers Identifies Potential Novel Drug Targets
Authors: Müller-Tidow Carsten , Schwäble Joachim , Steffen Björn , Tidow Nicola , Brandt Burkhardt , Becker Kerstin , Schulze-Bahr Eric , Halfter Hartmut , Vogt Ulf , Metzger Ralf , Schneider Paul M. , Büchner Thomas , Brandts Christian , Berdel Wolfgang E. , Serve Hubert 
Published: September 2005

Abstract
Novel high-throughput analyses in molecular biology allow sensitive and rapid identification of disease-related genes and drug targets. We have used quantitative real-time reverse transcription-PCR reactions (n = 23,000) to analyze expression of all human receptor tyrosine kinases (n = 56) in malignant tumors (n = 313) of different origins and normal control samples (n = 58). The different tumor types expressed very different numbers of receptor tyrosine kinases: whereas brain tumors and testicular cancer expressed 50 receptor tyrosine kinases, acute myeloid leukemia (AML) samples expressed only 20 different ones. Specimens of similar tumor origin exhibited characteristic receptor tyrosine kinase expression patterns and were grouped together in hierarchical cluster analyses. When we focused on specific tumor entities, receptor tyrosine kinases were identified that were disease and/or stage specific. Leukemic blasts from AML bone marrow samples differed significantly in receptor tyrosine kinase expression compared with normal bone marrow and purified CD34+ cells. Among the differentially expressed receptor tyrosine kinases, we found FLT3, c-kit, CSF1 receptor, EPHB6, leukocyte tyrosine kinase, and ptk7 to be highly overexpressed in AML samples. Whereas expression changes of some of these were associated with altered differentiation patterns (e.g., CSF1 receptor), others, such as FLT3, were genuinely overexpressed in leukemic blasts. These data and the associated database (http://medweb.uni-muenster.de/institute/meda/research/) provide a comprehensive view of receptor tyrosine kinase expression in human cancer. This information can assist in the definition of novel drug targets.
Defective Expression of Transforming Growth Factor β Receptor Type II Is Associated with CpG Methylated Promoter in Primary Non-Small Cell Lung Cancer
Authors: Zhang Hong-Tao , Chen Xiao-Feng , Wang Ming-Hua , Wang Jiu-Cun , Qi Qing-Yuan , Zhang Rong-Mei , Xu Wei-Qing , Fei Qing-Yan , Wang Fei , Cheng Qi-Qun , Chen Feng , Zhu Cheng-Song , Tao Shi-Heng , Luo Zewei 
Published: September 2005

Abstract
Purpose: Reduced expression of the transforming growth factor β receptor type II (TGFβRII), a key inhibitor of epithelial cell growth and tumor suppressor gene, was reported frequently in many types of tumors including non-small cell lung cancer (NSCLC). This study explored the significance of the TGFβRII gene in NSCLC carcinogenesis.
Experimental Design: With 43 independent pairs of tumor and paracarcinoma tissue samples from patients with primary NSCLC, we carried out PCR-denaturing gradient gel electrophoresis screening for DNA variants over the coding sequence of the TGFβRII gene, immunohistochemical assay of TGFβRII expression, methylation-specific PCR analysis, and semiquantitative reverse transcription-PCR.
Results: The PCR-denaturing gradient gel electrophoresis did not detect variation in the whole coding sequence of the TGFβRII gene, but the immunohistochemistry experiment revealed reduced or lost expression of the gene in 44% (19 of 43) of the tumor samples. The methylation analysis on the 19 pairs detected the frequent occurrence of methylated TGFβRII promoter in tumor tissues, whereas most of the paracarcinoma tissues were free of methylation. The reduced TGFβRII expression was highly significantly associated with the methylation event (P &lt; 10−4). The reverse transcription-PCR analysis demonstrated a clear agreement between reduced TGFβRII expression and decreased mRNA level of the gene in the tumor tissue samples.
Conclusions: TGFβRII plays an important role as a tumor suppressor in NSCLC carcinogenesis. The defective expression may serve as one of most important molecular mechanisms in explaining progression of the disease. In particular, aberrant 5′ CpG methylation of the gene has explained the down-regulation of the gene at a transcriptional level.
Hypermethylation of the
Retinoic Acid Receptor
-β
2
Gene in Head and Neck Carcinogenesis
Authors: Youssef Emile M. , Lotan Dafna , Issa Jean-Pierre , Wakasa Kenichi , Fan You-Hong , Mao Li , Hassan Khaled , Feng Lei , Lee J. Jack , Lippman Scott M. , Hong Waun K. , Lotan Reuben 
Published: September 2005

Abstract
Purpose: Retinoic acid receptor-β2 (RAR-β2) expression is suppressed in oral premalignant lesions and head and neck squamous cell carcinomas (HNSCCs). This study was conducted to determine whether RAR-β2 gene expression in such lesions can be silenced by promoter methylation.
Experimental Design: RAR-β2 methylation was analyzed in DNA samples from 22 pairs of primary HNSCC and adjacent normal epithelium, 124 samples of oral leukoplakia, and 18 HNSCC cell lines using methylation-specific PCR. RAR-β2 promoter was methylated in 67, 56, and 53% of HNSCC tumors, HNSCC cell lines, and microdissected oral leukoplakia specimens, respectively. RAR-β2 hypermethylation was confirmed by sodium bisulfite-PCR combined with restriction enzyme digestion analysis and by random cloning and sequencing of bisulfite-treated DNA isolates.
Results: Significantly higher RAR-β2 hypermethylation levels were found in tumor tissue compared with adjacent normal tissue (P = 0.002). RAR-β2 methylation in the cell lines was correlated with loss of RAR-β2 expression (P = 0.013) and inversely related to the presence of mutated p53 (P = 0.025). The demethylating agent 5-aza-2′-deoxycytidine (5-aza-CdR) restored RAR-β2 inducibility by all-trans-retinoic acid (ATRA) in some of the cell lines, which posses a methylated RAR-β2 promoter. In some cell lines, this effect was associated with increased growth inhibition after combined treatment with 5-aza-CdR and ATRA.
Conclusions: RAR-β2 silencing by methylation is an early event in head and neck carcinogenesis; 5-Aza-CdR can restore RAR-β2 inducibility by ATRA in most cell lines, and the combination of 5-aza-CdR and ATRA is more effective in growth inhibition than single agents.
Down-Regulation of BRCA1 in Chronic Pancreatitis and Sporadic Pancreatic Adenocarcinoma
Authors: Beger Carmela , Ramadani Marco , Meyer Stephan , Leder Gerd , Krüger Martin , Welte Karl , Gansauge Frank , Beger Hans G. 
Published: September 2005

Abstract
Purpose: BRCA1 and BRCA2 are considered to be breast cancer susceptibility genes that may also contribute to pancreatic cancer development because family studies revealed mutation carriers to have an increased risk of developing pancreatic cancer. However, as demonstrated for breast and ovarian cancer, inactivation of BRCA in sporadic diseases is based on alteration in gene expression or functional alteration.
Experimental Design: To study a potential correlation of BRCA1 and BRCA2 to chronic pancreatitis and development of sporadic pancreatic adenocarcinoma, we have analyzed the expression of these genes by quantitative PCR and performed immunohistochemical analyses in normal pancreatic tissues, chronic pancreatitis, and pancreatic cancer specimens.
Results: BRCA1 expression was down-regulated in chronic alcoholic pancreatitis, in particular on the RNA level. Furthermore, our data indicate suppressed BRCA1 expression in pancreatic cancer on both the RNA and protein levels. Quantitative analysis of BRCA1 protein expression demonstrated regular staining in 50% of tumor specimens tested and reduced staining in 50% of tumor specimens tested. Correlation with the clinical outcome revealed a significantly better 1-year overall survival for patients with BRCA1-regular as compared with BRCA1-reduced or BRCA1-absent tumors. In contrast, no substantial differences in BRCA2 expression were found in chronic pancreatitis and pancreatic cancer samples.
Conclusions: Our data demonstrate alteration of BRCA1 expression in chronic pancreatitis and sporadic pancreatic adenocarcinoma. We, for the first time, provide evidence for a role of BRCA1 in pancreatic carcinogenesis of noninherited tumors and for clinical outcome.
Prognostic Value of Combined “Triple”-Reverse Transcription-PCR Analysis for Prostate-Specific Antigen, Human Kallikrein 2, and Prostate-Specific Membrane Antigen mRNA in Peripheral Blood and Lymph Nodes of Prostate Cancer Patients
Authors: Kurek Ralf , Nunez German , Tselis Nikolaos , Konrad Lutz , Martin Thomas , Roeddiger Sandra , Aumüller Gerd , Zamboglou Nikolaos , Lin Daniel W. , Tunn Ulf W. , Renneberg Heiner 
Published: September 2005

Abstract
Purpose: We present the largest study of both peripheral blood and lymph node samples examining the utility of reverse transcription-polymerase chain reaction (RT-PCR) for established molecular markers as a diagnostic tool in the molecular staging of prostate cancer patients undergoing radical prostatectomy.
Experimental Design: Peripheral blood from 358 patients was obtained before radical prostatectomy. Corresponding obturatory lymph node samples were collected from 153 of these patients. Nested RT-PCR for prostate-specific antigen (PSA), human kallikrein 2 (hK2), and prostate-specific membrane antigen (PSMA) were performed on cDNA from peripheral blood. The lymph node cDNA was analyzed for PSA und hK2 expression.
Results: RT-PCR in peripheral blood was positive in 124 (34.6%) of 358 samples for PSA, 215 (60.1%) of 358 for PSMA, and 97 (27.1%) of 358 for hK2. Comparison of positive RT-PCR rates of pT2 and pT3 tumors in corresponding peripheral blood for PSA, PSMA, and hK2 were 31.9 and 40.0%, 58.8 and 62.5%, and 26.9 and 27.5%, respectively. Histopathologically, cancer-free lymph node samples were positive in RT-PCR for PSA and hK2 in 70 (49.6%) of 141 and 89 (63.2%) of 141 of cases. All histologically positive lymph node samples (n = 12, pN+) were positive for PSA RT-PCR. PSA RT-PCR alone, as well as combined PSA/PSMA RT-PCR evaluation, in peripheral blood showed a significant association with grading. PSA RT-PCR lymph node-negative samples were significantly less likely positive in their corresponding peripheral blood RT-PCR sample.
Conclusions Although the preoperative PSA RT-PCR in peripheral blood correlated with the grading of prostate cancer, no combination of RT-PCR results using “triple” markers (PSA, hK2, PSMA) in peripheral blood and/or lymph nodes yielded additional preoperative staging information.
Impairment of Both Apoptotic and Cytoprotective Signalings in Glioma Cells Resistant to the Combined Use of Cisplatin and Tumor Necrosis Factor α
Authors: Duan Lian , Aoyagi Masaru , Tamaki Masashi , Yoshino Yoshikazu , Morimoto Takashi , Wakimoto Hiroaki , Nagasaka Yasuhiko , Hirakawa Kimiyoshi , Ohno Kikuo , Yamamoto Kiyotaka 
Published: September 2005

Abstract
Purpose: Tumor necrosis factor (TNF)-α elicits two opposing effects, the induction of apoptosis and the transcription of antiapoptotic genes. We have recently shown that cisplatin sensitizes glioma cells to TNF-induced apoptosis, but only in some cell lines. To understand the mechanism involved in the different susceptibilities, we examined both the activation of caspases and cytoprotective signaling by TNF-α.
Experimental Design: Caspase activation was examined by estimating the cleavage of substrate peptides and by immunoblot to identify the cleavage of procaspases. Peptide inhibitors of caspases were used to reverse the cytotoxicity. The binding of TNF-α to the receptor was analyzed by flow cytometry. Nuclear factor (NF)-κB activation was assayed by the binding of NF-κB to oligonucleotides containing the consensus binding site. Interleukin (IL)-1β, IL-6, IL-8, and manganous superoxide dismutase (MnSOD) were measured by enzyme-linked immunoassays.
Results: T98G and U87MG underwent apoptosis on treatment with cisplatin and TNF-α, but U373MG and A172 were resistant. Caspases 2, 3, and 6–10, but not caspases 1, 4, and 5, were activated in sensitive cells, and none were activated in resistant cells. The binding of TNF-α to the receptor was the same in all four of the cell lines. In the sensitive cells, NF-κB activation and the production of IL-1β, IL-6, IL-8, and MnSOD were significantly elevated by TNF-α. However, in the resistant cells, the production of IL-1β and IL-6 were specifically impaired in response to TNF-α.
Conclusions: Our results indicate that both apoptotic and cytoprotective pathways are impaired in glioma cells that are resistant to treatment with cisplatin and TNF-α.
Pilot Study Evaluating the Pharmacokinetics, Pharmacodynamics, and Safety of the Combination of Exemestane and Tamoxifen
Authors: Rivera Edgardo , Valero Vicente , Francis Deborah , Asnis Aviva G. , Schaaf Larry J. , Duncan Barbara , Hortobagyi Gabriel N. 
Published: September 2005

Abstract
Purpose: We conducted a pilot study assessing the effects of the selective estrogen receptor modulator, tamoxifen, on the pharmacokinetics, pharmacodynamics, and safety of the steroidal, irreversible aromatase inhibitor (AI), exemestane, when the two were coadministered in postmenopausal women with metastatic breast cancer.
Experimental Design: Patients with documented or unknown hormone receptor sensitivity were eligible. Patients received oral exemestane at 25-mg once daily. Starting day 15, oral tamoxifen at 20-mg once daily, was added. We measured plasma concentrations of exemestane, estrone, estrone sulfate, and estradiol after 14 days of exemestane monotherapy and after ∼4 weeks of combination therapy. The incidence and severity of adverse events were assessed by physical examination and patient reporting.
Results: We treated 18 patients. All had received prior chemotherapy and/or hormonal therapy, eight and six, respectively, with single-agent selective estrogen receptor modulators or irreversible aromatase inhibitors; no hormonal therapy was given within 30 days of study entry. Plasma exemestane concentrations and estrone, estrone sulfate, and estradiol suppression were unchanged after ∼4 weeks of tamoxifen coadministration. All drug-related adverse events were grades 1 or 2; none was unexpected. Although not a formal study end point, antitumor activity was noted, with two partial responses and four cases of stable disease among 17 evaluable patients after a 9-month median follow-up (range, 2.5–19 months).
Conclusions: This pilot study provides evidence that coadministration of tamoxifen does not affect exemestane pharmacokinetics or pharmacodynamics and that the combination is well-tolerated and active. Further clinical investigation is warranted.
Randomized, Double-Blind, Placebo-Controlled Phase IIB Trial of the Cyclooxygenase Inhibitor Ketorolac as an Oral Rinse in Oropharyngeal Leukoplakia
Authors: Mulshine James L. , Atkinson Jane C. , Greer Robert O. , Papadimitrakopoulou Vassiliki A. , Van Waes Carter , Rudy Susan , Martin Jack W. , Steinberg Seth M. , Liewehr David J. , Avis Ingalill , Linnoila R. Ilona , Hewitt Stephen , Lippman Scott M. , Frye Robin , Cavanaugh Paul F. 
Published: September 2005

Abstract
Purpose: Nonselective cyclooxygenase (COX) inhibitors have been reported to decrease the frequency of upper aerodigestive cancers. Ketorolac tromethamine oral rinse has been shown to resolve another COX-dependent process, periodontal disease, without incurring gastrointestinal side effects. This trial evaluated if a topically delivered oral rinse containing ketorolac was as safe as and more effective than oral rinse alone in reducing the area of oral leukoplakia.
Experimental Design: 57 patients were randomized (2:1 ratio) in a double-blind, placebo-controlled study of ketorolac (10 ml of a 0.1% ketorolac rinse solution; n = 38) or placebo (10 ml of rinse solution; n = 19) given twice daily for 30 s over 90 days. Primary end point was evaluated visually obtaining bidimensional measurement of the size of leukoplakia lesion(s) at entry and at 90 days. Secondary end point was histological assessment of the leukoplakia as sampled by serial punch biopsy and independently reviewed by three pathologists.
Results: The patients included 67% males, 11% non-Caucasian, and 86% used tobacco with no significant differences between the two arms. Both rinses were well tolerated with good compliance, and there was no significant difference in adverse events (P = 0.27). Major response rate (complete response and partial response) was 30% for ketorolac and 32% for the placebo arm. There was no significant difference in change in histology between the two arms.
Conclusion: Local delivery of a COX-containing oral rinse was well tolerated but produced no significant reduction in the extent of leukoplakia compared with the placebo. However, the favorable response rate to placebo arm remains unexplained and additional investigation of the tissue penetration with ketorolac is warranted.
Role of Expression of Focal Adhesion Kinase in Progression of Hepatocellular Carcinoma
Authors: Itoh Shinji , Maeda Takashi , Shimada Mitsuo , Aishima Shin-ichi , Shirabe Ken , Tanaka Shinji , Maehara Yoshihiko 
Published: September 2005

Abstract
Purpose: Although hepatocellular carcinoma (HCC) is the most common cancer of the human liver, the mechanisms that regulate HCC development and progression remain unclear. The aim of this study was to investigate whether focal adhesion kinase (FAK) is involved in the progression of human HCC.
Experimental Design: Western blot analysis for FAK was performed on three HCC cell lines. We reviewed 64 consecutive patients who had undergone initial liver resection for HCC without preoperative treatment. Immunohistochemistry analysis for FAK was performed on paraffin-embedded tissues. FAK expression was confirmed by Western blot analysis in several clinical samples. We investigated the correlation between FAK expression and clinical outcome.
Results: FAK proteins were detected in all HCC cell lines. Hepatocytes in the normal liver and chronic hepatitis with or without cirrhosis were negative for immunohistochemical staining for FAK expression. Cytoplasmic FAK expression was observed in 18 of 64 patients (28.1%), and this positive staining was correlated with gender (P &lt; 0.05), a lower level of serum albumin (P &lt; 0.05), and portal venous invasion (P &lt; 0.01). Positive staining for FAK was associated with significantly poorer survival (P &lt; 0.05). In multivariate analysis, FAK overexpression was an independent factor in determining the prognosis of patients.
Conclusions: These data suggest that FAK plays an important role in promoting tumor progression, especially vascular invasion, in HCC. FAK could play an important role in HCC progression and would be a novel target for HCC therapeutics as well as a prognostic marker.
Overexpression and Amplification of Aurora-A in Hepatocellular Carcinoma
Authors: Jeng Yung-Ming , Peng Shian-Yang , Lin Chiao-Ying , Hsu Hey-Chi 
Published: September 2005

Abstract
Purpose: Aurora-A/STK15/BTAK, a centrosome-associated serine/threonine kinase, has been shown to induce chromosomal instability, leading to aneuploidy and cell transformation. The purpose of this study was to investigate the expression and amplification of Aurora-A in hepatocellular carcinoma (HCC).
Experimental Design: Aurora-A mRNA levels were measured in 224 HCCs and 199 paired nontumorous liver tissues by reverse transcription-PCR. Aurora-A mRNA and protein levels of 8 were also measured by reverse transcription-PCR and Western blot hybridization in 8 liver cancer cell lines. Amplification of Aurora-A was determined by Southern blot hybridization in 99 cases.
Results: Aurora-A was overexpressed in 137 of 224 (61%) HCCs and all 8 of the cell lines. Overexpression of Aurora-A was associated with high-grade (grade II-IV), and high-stage (stage IIIB-IV) tumors, p53 mutation, infrequent β-catenin mutation, and poor outcome. Aurora-A overexpression and p53 mutation acted synergistically toward poor prognosis. Amplification of Aurora-A was detected only in 3 HCCs.
Conclusion: The results show that Aurora-A is overexpressed frequently in HCC, and correlated with high grade and high stage, indicating that overexpression of Aurora-A plays a role in the development and progression of HCC.
Gene Expression Profiling after Radiation-Induced DNA Damage Is Strongly Predictive ofBRCA1Mutation Carrier Status
Authors: Kote-Jarai Zsofia , Williams Richard D. , Cattini Nicola , Copeland Maria , Giddings Ian , Wooster Richard , tePoele Robert H. , Workman Paul , Gusterson Barry , Peacock John , Gui Gerald , Campbell Colin , Eeles Ros 
Published: September 2005

AbstractPurpose: The impact of the presence of a germ-line BRCA1 mutation on gene expression in normal breast fibroblasts after radiation-induced DNA damage has been investigated.Experimental Design: High-density cDNA microarray technology was used to identify differential responses to DNA damage in fibroblasts from nine heterozygous BRCA1 mutation carriers compared with five control samples without personal or family history of any cancer. Fibroblast cultures were irradiated, and their expression profile was compared using intensity ratios of the cDNA microarrays representing 5603 IMAGE clones.Results: Class comparison and class prediction analysis has shown that BRCA1 mutation carriers can be distinguished from controls with high probability (∼85%). Significance analysis of microarrays and the support vector machine classifier identified gene sets that discriminate the samples according to their mutation status. These include genes already known to interact with BRCA1 such as CDKN1B, ATR, and RAD51.Conclusions: The results of this initial study suggest that normal cells from heterozygous BRCA1 mutation carriers display a different gene expression profile from controls in response to DNA damage. Adaptations of this pilot result to other cell types could result in the development of a functional assay for BRCA1 mutation status.