bluuebunny/crossref_metadata_2025_split huggingface dataset:
RNA Interference Suppression of MUC1 Reduces the Growth Rate and Metastatic Phenotype of Human Pancreatic Cancer Cells
Authors: Tsutsumida Hideaki , Swanson Benjamin J. , Singh Pankaj K. , Caffrey Thomas C. , Kitajima Shinichi , Goto Masamichi , Yonezawa Suguru , Hollingsworth Michael A. 
Published: May 2006

Abstract
MUC1 is a highly glycosylated, type I transmembrane protein expressed by normal ductal epithelial cells of the pancreas, breast, lung, and gastrointestinal tract, and overexpressed in many cases of adenocarcinoma. We down-regulated MUC1 expression by RNA interference and investigated the effects on malignant and metastatic potential of a human pancreatic cancer cell line, S2-013. MUC1-suppressed clones, S2-013.MTII.C1 and S2-013.MTII.C2, were established by targeting a sequence 3,151 bp from the initiation codon and characterized in vitro for proliferation, invasion, and adhesion. We evaluated the effects of MUC1 suppression in vivo on tumor growth and metastatic properties following implantation into the cecum or pancreas of athymic mice. MUC1-suppressed clones showed significantly decreased proliferation in vitro and in vivo. Global gene expression was evaluated by oligonucleotide microarray analysis. Surprisingly, genes predicted to increase doubling times (cyclin B1 and cyclin D3) were overexpressed in MUC1-suppressed clones. There were alterations in expression of several genes that may affect the malignant properties of pancreatic cancer. Adhesion of MUC1-suppressed cells in vitro to type IV collagen and fibronectin was slightly increased, and adhesion was slightly decreased to type I collagen and laminin. Results of implantation to cecum and pancreas showed significant reduction of metastasis to lymph nodes, lung, or peritoneal sites compared with S2-013.gfp-neo control cells. These results support the hypothesis that MUC1 contributes significantly to growth and metastasis, and that down-regulation of MUC1 protein expression decreases the metastatic potential of pancreatic adenocarcinoma.
Glucocorticoids Suppress Tumor Angiogenesis and In vivo Growth of Prostate Cancer Cells
Authors: Yano Akihiro , Fujii Yasuhisa , Iwai Aki , Kageyama Yukio , Kihara Kazunori 
Published: May 2006

Abstract
Purpose: Glucocorticoids, such as prednisone, hydrocortisone, and dexamethasone, are known to produce some clinical benefit for patients with hormone-refractory prostate cancer (HRPC). However, the underlying mechanisms by which glucocorticoids affect HRPC growth are not well established as yet. Here, we hypothesize that the therapeutic effect of glucocorticoids on HRPC can be attributed to a direct inhibition of angiogenesis through the glucocorticoid receptor by down-regulating two major angiogenic factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8).
Experimental Design: The effects of dexamethasone on VEGF and IL-8 expression and cell proliferation were examined using DU145, which expresses glucocorticoid receptor. The effects of dexamethasone on DU145 xenografts were determined by analyzing VEGF and IL-8 gene expression, microvessel density, and tumor volume.
Results: Dexamethasone significantly down-regulated VEGF and IL-8 gene expression by 50% (P &lt; 0.001) and 89% (P &lt; 0.001), respectively, and decreased VEGF and IL-8 protein production by 55% (P &lt; 0.001) and 74% (P &lt; 0.001), respectively, under normoxic condition. Similarly, hydrocortisone down-regulated VEGF and IL-8 gene expression. The effects of dexamethasone were completely reversed by the glucocorticoid receptor antagonist RU486. Even under hypoxia-like conditions, dexamethasone inhibited VEGF and IL-8 expression. In DU145 xenografts, dexamethasone significantly decreased tumor volume and microvessel density and down-regulated VEGF and IL-8 gene expression, whereas dexamethasone did not affect the in vitro proliferation of the cells.
Conclusion: Glucocorticoids suppressed androgen-independent prostate cancer growth possibly due to the inhibition of tumor-associated angiogenesis by decreasing VEGF and IL-8 production directly through glucocorticoid receptor in vivo.
Phase II Clinical Trial Results Involving Treatment with Low-Dose Daily Oral Cyclophosphamide, Weekly Vinblastine, and Rofecoxib in Patients with Advanced Solid Tumors
Authors: Young Scott D. , Whissell Mark , Noble Jonathan C.S. , Cano Pablo O. , Lopez Pedro G. , Germond Colin J. 
Published: May 2006

Abstract
Purpose: Preclinical studies indicate that conventional chemotherapeutic agents given continuously at low doses (metronomic chemotherapy) may provide an improved therapeutic index. Cyclophosphamide and vinblastine have been best studied in experimental models, where tumor growth inhibition is achieved, at least in part, through antiangiogenic mechanisms.
Experimental Design: Fifty patients with advanced solid tumors were enrolled in this phase II trial, 43 of whom had received at least one prior chemotherapy regimen. Patients were required to have Eastern Cooperative Oncology Group performance status of ≤2, a life expectancy of &gt;3 months, and at least one measurable lesion. All patients received oral cyclophosphamide (50 mg) and rofecoxib (25 mg) daily in addition to weekly injections of vinblastine (3 mg/m2). Half of the patients also received minocycline (100 mg) orally twice daily with the intent of further inhibiting tumor angiogenesis. The primary end point of the study was clinical benefit, defined as the percentage of patients experiencing an objective response or exhibiting stable disease for at least 6 months.
Results: For the 47 eligible patients, there were two (4%) complete responses and four (9%) partial responses, for an overall objective response rate of 13%. An additional eight patients achieved disease stabilization (stable disease ≥6 months) (17%). The primary end point of clinical benefit was therefore 30%, (95% confidence interval, 16-44%). The median progression-free survival for all patients was 103 days and 289 days for patients experiencing clinical benefit. The incidence of patients experiencing grade 3/4 toxicities were as follows: neutropenia (10/2), anemia (2/0), and thrombocytopenia (1/0). No patients developed grade 3 or 4 nausea, vomiting, mucositis, or alopecia.
Conclusions: This low-dose regimen consisting of daily oral cyclophosphamide and weekly vinblastine injections given concurrently with rofecoxib is associated with minimal toxicity and provides significant clinical benefit to patients with advanced solid tumors. These results are particularly encouraging given the nature of the study population and indicate that this approach merits further investigation in specific disease site studies.
Phase I Trial of the Trifunctional Anti-HER2 × Anti-CD3 Antibody Ertumaxomab in Metastatic Breast Cancer
Authors: Kiewe Philipp , Hasmüller Stephan , Kahlert Steffen , Heinrigs Maja , Rack Brigitte , Marmé Alexander , Korfel Agnieszka , Jäger Michael , Lindhofer Horst , Sommer Harald , Thiel Eckhard , Untch Michael 
Published: May 2006

AbstractPurpose: Ertumaxomab is an intact bispecific antibody targeting HER2/neu and CD3 with selective binding to activatory Fcγ type I/III receptors, resulting in the formation of a tri-cell complex between tumor cells, T cells, and accessory cells. Patients with metastatic breast cancer were enrolled into a multicenter phase I dose-escalating trial.Experimental Design: Three ascending doses of ertumaxomab (10-200 μg) were administered i.v. on day 1, 7 ± 1, and 13 ± 1. Safety and tolerability were the primary objectives. Secondary objectives were antitumor activity and different immunologic variables.Results: Fifteen out of 17 enrolled patients completed the study. One hundred micrograms was identified as the maximal tolerable single dose. Most drug-related adverse events were mild and transient including fever (94%), rigors (47%), headache (35%), nausea (29%), vomiting (29%). Grades 3 and 4 (Common Toxicity Criteria) were lymphocytopenia (76%) and elevation of liver enzymes (47%). One patient (200 μg dose) developed severe hypotension and respiratory distress syndrome, another patient (150 μg dose) developed a systemic inflammatory response syndrome and acute renal failure. Aggravation of congestive heart failure was seen in one patient with preexisting ventricular dysfunction after administration of the third dose (200 μg). All adverse events were fully reversible. Antitumor response was seen in 5 out of 15 evaluable patients (one with a complete response, two with partial responses, two with stable disease) at dose levels of ≥100 μg. Measurements of cytokines (interleukin-6, interleukin-2, tumor necrosis factor-α, and IFN-γ) suggest a strong T helper cell type 1–associated immune response. The induction of human anti-mouse/anti-rat antibodies was detected in 5 out of 16 (31%) patients.Discussion: Treatment with triple infusions of ertumaxomab yields a strong immunologic response. Doses up to 100 μg can be safely infused with close monitoring of patients. The observed clinical responses are encouraging and indicate antitumor efficacy.
Effects of Helicobacter pylori Eradication on Methylation Status of E-Cadherin Gene in Noncancerous Stomach
Authors: Leung Wai K. , Man Ellen P.S. , Yu Jun , Go Minnie Y.Y. , To Ka-fai , Yamaoka Yoshio , Cheng Victoria Y.Y. , Ng Enders K.W. , Sung Joseph J.Y. 
Published: May 2006

Abstract
Purpose: Promoter hypermethylation of E-cadherin plays an important role on gastric cancer development. Whereas E-cadherin methylation was frequently detected in the stomach of Helicobacter pylori–infected individuals, we tested whether eradication of H. pylori alters the methylation status of the noncancerous gastric epithelium.
Experimental Design: Endoscopic biopsies were taken from the antrum and corpus of H. pylori–infected subjects without gastric cancer. Presence of methylated E-cadherin sequences in the gastric specimens was detected by methylation-specific PCR. Bisulfite DNA sequencing was done to determine the topographical distribution and changes in methylation profiles with H. pylori eradication.
Results: Among the 28 H. pylori–infected subjects (median age, 44.5 years), 15 (53.6%) had E-cadherin methylation detected in stomach at baseline. Discordant methylation patterns between the antrum and corpus were noted in six patients. One year after successful H. pylori eradication, there was a significant reduction in the methylation density of the promoter region and exon 1 of the E-cadherin gene as detected by bisulfite DNA sequencing (P &lt; 0.001).
Conclusion: Promoter methylation in E-cadherin was frequently detected in the stomach of H. pylori–infected individuals. Eradication of H. pylori might possibly reduce the methylation density in E-cadherin gene and the chance of subsequent neoplastic transformation.
Detection and Functional Analysis of CD8+ T Cells Specific for PRAME: a Target for T-Cell Therapy
Authors: Griffioen Marieke , Kessler Jan H. , Borghi Martina , van Soest Ronald A. , van der Minne Caroline E. , Nouta Jan , van der Burg Sjoerd H. , Medema Jan Paul , Schrier Peter I. , Falkenburg J.H. Frederik , Osanto Susanne , Melief Cornelis J.M. 
Published: May 2006

AbstractPurpose: Preferentially expressed antigen on melanomas (PRAME) is an interesting antigen for T-cell therapy because it is frequently expressed in melanomas (95%) and other tumor types. Moreover, due to its role in oncogenic transformation, PRAME-negative tumor cells are not expected to easily arise and escape from T-cell immunity. The purpose of this study is to investigate the usefulness of PRAME as target for anticancer T-cell therapies.Experimental Design: HLA-A*0201-subtyped healthy individuals and advanced melanoma patients were screened for CD8+ T cells directed against previously identified HLA-A*0201-binding PRAME peptides by IFN-γ enzyme-linked immunosorbent spot assays and tetramer staining. PRAME-specific T-cell clones were isolated and tested for recognition of melanoma and acute lymphoid leukemia (ALL) cell lines. PRAME mRNA expression was determined by quantitative real-time reverse transcription-PCR.Results: In 30% to 40% of healthy individuals and patients, PRA100-108-specific CD8+ T cells were detected both after in vitro stimulation and directly ex vivo after isolation by magnetic microbeads. Although CD45RA− memory PRA100-108-specific T cells were found in some individuals, the majority of PRA100-108-tetramer+ T cells expressed CD45RA, suggesting a naive phenotype. PRA100-108-tetramer+ T-cell clones were shown to recognize and lyse HLA-A*0201+ and PRAME+ melanoma but not ALL cell lines. Quantitative real-time reverse transcription-PCR showed significantly lower PRAME mRNA levels in ALL than in melanoma cell lines, suggesting that PRAME expression in ALL is below the recognition threshold of our PRA100-108-tetramer+ T cells.Conclusion: These data support the usefulness of PRAME and in particular the PRA100-108 epitope as target for T-cell therapy of PRAME-overexpressing cancers.
Fenretinide Activity in Retinoid-Resistant Oral Leukoplakia
Authors: Lippman Scott M. , Lee J. Jack , Martin Jack W. , El-Naggar Adel K. , Xu Xiaochun , Shin Dong M. , Thomas Margaret , Mao Li , Fritsche Herbert A. , Zhou Xian , Papadimitrakopoulou Vassiliki , Khuri Fadlo R. , Tran Hai , Clayman Gary L. , Hittelman Walter N. , Hong Waun Ki , Lotan Reuben 
Published: May 2006

AbstractPurpose: To test the hypothesis that the retinamide N-(4-hydroxyphenyl)retinamide (fenretinide) would be clinically active potentially via receptor-independent apoptosis and receptor-dependent effects in natural retinoid-resistant oral leukoplakia patients—the first test of this hypothesis in any in vivo setting.Experimental Design: A phase II trial of fenretinide (200 mg/d for 3 months) in oral leukoplakia patients who had not responded (de novo resistance) or who had responded and then relapsed (acquired resistance) to previous treatment with natural retinoids. We analyzed apoptosis via the terminal deoxynucleotidyl transferase–mediated nick end labeling in situ DNA fragmentation assay.Results: We accrued 35 evaluable patients with retinoid-resistant oral leukoplakia, 12 (34.3%) had partial responses to fenretinide (95% confidence interval, 19.2-52.4%), and response was associated with acquired resistance to natural retinoids (P = 0.015, Fisher's exact test). Nine responders progressed within 9 months of stopping fenretinide. Toxicity was minimal and compliance was excellent. Mean apoptosis values (SE) increased from 0.35% (0.25%) at baseline to 1.18% (0.64%) at 3 months (P = 0.001, sign test); this increase did not correlate with clinical response. The increases in 3-month mean serum concentrations of fenretinide (0.23 μmol/L) and N-(4-methoxyphenyl)retinamide (0.57 μmol/L) correlated with decreased retinol concentrations [Spearman correlation coefficient of −0.57 (P = 0.001) and −0.43 (P = 0.01), respectively].Conclusions: Low-dose fenretinide was clinically active and produced a small increase in apoptosis in retinoid-resistant oral leukoplakia.
Immunogenic HLA-B*0702-Restricted Epitopes Derived from Human Telomerase Reverse Transcriptase That Elicit Antitumor Cytotoxic T-Cell Responses
Authors: Adotévi Olivier , Mollier Karine , Neuveut Christine , Cardinaud Sylvain , Boulanger Emmanuelle , Mignen Blandine , Fridman Wolf-Hervé , Zanetti Maurizio , Charneau Pierre , Tartour Eric , Lemonnier François , Langlade-Demoyen Pierre 
Published: May 2006

AbstractPurpose: The human telomerase reverse transcriptase (hTERT) is considered as a potential target for cancer immunotherapy because it is preferentially expressed in tumor cells. To increase the applicability of hTERT-based immunotherapy, we set out to identify CTL epitopes in hTERT restricted by HLA-B*0702 molecule, a common MHC class I allele.Experimental Design: HLA-B*0702-restricted peptides from hTERT were selected by using a method of epitope prediction and tested for their immunogenicity in human (in vitro) and HLA-B*0702 transgenic mice (in vivo).Results: All the six hTERT peptides that were predicted to bind to HLA-B*0702 molecule were found to induce primary human CTL responses in vitro. The peptide-specific CD8+ CTL lines were tested against various hTERT+ tumor cells. Although differences were observed according to the tumor origin, only three CTL lines specific for p277, p342, and p351 peptides exhibited cytotoxicity against tumor cells in a HLA-B*0702-restricted manner. In addition, this cytotoxicity was inhibited by the addition of peptide-loaded cold target cells and indicated that these epitopes are naturally processed and presented on the tumor cells. Further, in vivo studies using humanized HLA-B*0702 transgenic mice showed that all the candidate peptides were able to induce CTL responses after peptide immunization. Furthermore, vaccination with a plasmid DNA encoding full-length hTERT elicited peptide-specific CTL responses, indicating that these epitopes are efficiently processed in vivo.Conclusions: Together with previously reported hTERT epitopes, the identification of new CTL epitopes presented by HLA-B*0702 increases the applicability of hTERT-based immunotherapy to treating cancer.
Evaluation of Toxicity following Electrically Mediated Interleukin-12 Gene Delivery in a B16 Mouse Melanoma Model
Authors: Heller Loree , Merkler Kathleen , Westover Jeffrey , Cruz Yolmari , Coppola Domenico , Benson Kaaron , Daud Adil , Heller Richard 
Published: May 2006

Abstract
Purpose: Interleukin-12 (IL-12) has potential as an immunotherapeutic agent for the treatment of cancer but is unfortunately associated with toxicity. Delivery of a plasmid encoding IL-12 with electroporation induces an antitumor effect in the B16 mouse melanoma model without serious side effects. To translate this observation to the clinic, an evaluation of toxicity was done in the mouse model.
Experimental Design: Weight change, tumor response, blood chemistry and hematology values, and serum IL-12 levels were evaluated. Multiple tissues were analyzed histopathologically.
Results: A pronounced reduction in tumor volume, including a large percentage of complete regressions, was observed after electrically mediated gene therapy. No significant increases in serum IL-12 levels were detected. Tumor-bearing mice showed an increased number of atypical hematology values when compared with normal naive controls. Statistically significant differences in chemistry and hematology values were observed sporadically in most of the standard chemistry and hematology categories in all groups. The only histopathologic abnormality specific to the animals receiving both plasmid and electroporation was inflammation associated with the kidney at the last time point.
Conclusions: In general, mice that received both plasmid and electroporation showed the least abnormal histopathologic findings and were found to be in the best health, reflecting the reduced burden of disease. No significant toxic effects due to the IL-12 gene therapy were observed.
Telomerase Template Antagonist GRN163L Disrupts Telomere Maintenance, Tumor Growth, and Metastasis of Breast Cancer
Authors: Hochreiter Amelia E. , Xiao Hongling , Goldblatt Erin M. , Gryaznov Sergei M. , Miller Kathy D. , Badve Sunil , Sledge George W. , Herbert Brittney-Shea 
Published: May 2006

Abstract
Purpose: Maintenance of telomeres by telomerase is critical for the continuing proliferation of most advanced cancer cells. Telomerase activity has been detected in the vast majority of cancer cells but not most normal cells, making the enzyme an attractive target for anticancer therapy. The aim of this study was to address the breast cancer translational potential of the novel telomerase inhibitor, GRN163L.
Experimental Design: In the present study, we investigated the effects of GRN163L treatment on a panel of breast cancer cells representing different tumor subtypes with varying genetic backgrounds, including ER+, ER−, HER2+, BRCA1 mutant breast tumor cells as well as doxorubicin-resistant cancer cells. To investigate the in vivo effects of GRN163L, we employed a breast cancer xenograft and metastasis model that simulates a clinical situation in which a patient arrives with a primary tumor that may be then treated or surgically removed.
Results: GRN163L effectively inhibited telomerase activity in a dose-dependent fashion in all breast cancer cell lines resulting in progressive telomere shortening. A mismatch control oligonucleotide showed no effect on telomerase activity and GRN163L did not significantly affect telomere shortening in normal human mammary epithelial cells or in endothelial cells. Breast cancer cells that exhibited telomerase inhibition also exhibited significant reduction in colony formation and tumorigenicity. Furthermore, GRN163L suppressed tumor growth and lung metastases (P = 0.017) of MDA-MB-231 cells in vivo after 4 weeks of treatment.
Conclusions: These results show in vivo effectiveness of GRN163L in breast cancer and support its promising clinical potential for breast cancer treatment.
Clinical and Immunologic Responses to Active Specific Cancer Vaccines in Human Colorectal Cancer
Authors: Nagorsen Dirk , Thiel Eckhard 
Published: May 2006

AbstractColorectal cancer is a common malignant disease, which, despite some progress, still requires improved therapeutic options. Several clinical studies have used active specific immunotherapy (i.e., vaccination) in colorectal cancer. However, the literature still lacks a comprehensive meta-analysis of this approach in advanced colorectal cancer. We did a systematic review with a meta-analysis of clinical studies to evaluate the objective clinical and immunologic response to active specific immunotherapy in patients with colorectal cancer. We conducted a search of Medline and the Web of Science, manually reviewed the literature, and consulted with experts. Criteria for including studies were colorectal cancer patients, active specific immunotherapy to induce a response directed against cancer or cancer antigens, an evaluable tumor burden (i.e., advanced or metastatic colorectal cancer), and precise classification of the patient, disease, and response. Response rates were assessed according to WHO criteria. Primary end points were the objective clinical response rate and the rate of immunologic responses. The secondary end point was the distribution of immune and clinical responses in relation to the route of vaccination and the type of vaccine. Thirty-two phase I/II studies reporting on 527 patients with advanced or metastatic colorectal cancer met all inclusion criteria. Pooled analysis showed an overall response rate (complete response + partial response) of 0.9% for advanced/metastatic colorectal cancer patients who underwent active specific immunization with a broad variety of substances (e.g., autologous tumor cells, peptide vaccine, dendritic cells, idiotypic antibody, and virus-based vaccine). Humoral immune responses were reported in 59%, and cellular ones were reported in 44% of the cases. Mixed or minor responses and disease stabilization are described in 1.9% and 8.3% of colorectal cancer patients, respectively. Pooled results of clinical trials reveal a very weak clinical response rate of &lt;1% for active specific immunization procedures currently available for advanced colorectal cancer. Immune response induction is described in approximately half the patients.