bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of Endothelial Nitric Oxide Synthase Expression by Melanoma Sensitizes Endothelial Cells to Tumor Necrosis Factor-Driven Cytotoxicity
Authors: Mocellin Simone , Provenzano Maurizio , Rossi Carlo Riccardo , Pilati Pierluigi , Scalerta Romano , Lise Mario , Nitti Donato 
Published: September 2005

AbstractPurpose: The cascade of molecular events leading to tumor necrosis factor (TNF)-mediated tumor regression is still incompletely elucidated. We investigated the role of endothelial nitric oxide synthase in determining the tumor-selective activity of TNF.Experimental Design: Using quantitative real-time PCR, endothelial nitric oxide synthase gene levels were measured in melanoma metastases of the skin and normal skin biopsies obtained from 12 patients before undergoing TNF-based therapy. In vitro, the ability of melanoma cells supernatant to affect endothelial nitric oxide synthase transcription by endothelial cells and the influence of nitric oxide synthase inhibition on TNF cytotoxicity toward endothelial cells was evaluated.Results: Endothelial nitric oxide synthase transcript abundance resulted significantly greater in tumor samples rather than in normal skin samples and in patients showing complete response to TNF-based treatment rather than in those showing partial/minimal response. In vitro, melanoma cells’ supernatant induced endothelial nitric oxide synthase gene expression by endothelial cells. Nitric oxide synthase inhibition slowed endothelial cells proliferation and, if induced before TNF administration, decreased the cytokine-mediated cytotoxicity on endothelial cells.Conclusions: Taken together, these findings support the hypothesis that high expression of endothelial nitric oxide synthase in the tumor microenvironment might increase or be a marker for endothelial cells sensitivity to TNF. These observations may have important prognostic and/or therapeutic implications in the clinical setting.
Combined Epidermal Growth Factor Receptor Targeting with the Tyrosine Kinase Inhibitor Gefitinib (ZD1839) and the Monoclonal Antibody Cetuximab (IMC-C225)
Authors: Matar Pablo , Rojo Federico , Cassia Raúl , Moreno-Bueno Gema , Di Cosimo Serena , Tabernero José , Guzmán Marta , Rodriguez Sonia , Arribas Joaquín , Palacios José , Baselga José 
Published: September 2005

AbstractPurpose: The epidermal growth factor receptor (EGFR) is abnormally activated in cancer and two classes of anti-EGFR agents, monoclonal antibodies and low-molecular-weight tyrosine kinase inhibitors, have shown antitumor activity in patients. Because these two classes of antireceptor agents target the EGFR at different sites, we decided to explore whether the combined administration of gefitinib, a tyrosine kinase inhibitor, and cetuximab, a monoclonal antibody, had superior antitumor activity than either agent given alone.Experimental Design: We studied the effects of the combination of gefitinib and cetuximab in a panel of human cancer cell lines and in an EGFR-dependent human tumor xenograft model (A431). The effects of these two agents on EGFR signaling, proliferation, apoptosis, and vascularization were evaluated. In addition, we analyzed, with cDNA arrays, changes in gene expression profiles induced by both agents.Results: The combined treatment with gefitinib and cetuximab resulted in a synergistic effect on cell proliferation and in superior inhibition of EGFR-dependent signaling and induction of apoptosis. In a series of in vivo experiments, single-agent gefitinib or cetuximab resulted in transient complete tumor remission only at the highest doses. In contrast, suboptimal doses of gefitinib and cetuximab given together resulted in a complete and permanent regression of large tumors. In the combination-treated tumors, there was a superior inhibition of EGFR, mitogen-activated protein kinase, and Akt phosphorylation, as well as greater inhibition of cell proliferation and vascularization and enhanced apoptosis. Using cDNA arrays, we found 59 genes that were coregulated and 45 genes differentially regulated, including genes related to cell proliferation and differentiation, transcription, DNA synthesis and repair, angiogenesis, signaling molecules, cytoskeleton organization, and tumor invasion and metastasis.Conclusions: Our findings suggest both shared and complementary mechanisms of action with gefitinib and cetuximab and support combined EGFR targeting as a clinically exploitable strategy.
Recognition of Adult T-Cell Leukemia/Lymphoma Cells by CD4+ Helper T Lymphocytes Specific for Human T-Cell Leukemia Virus Type I Envelope Protein
Authors: Kobayashi Hiroya , Nagato Toshihiro , Yanai Mitsuru , Oikawa Kensuke , Sato Keisuke , Kimura Shoji , Tateno Masatoshi , Omiya Ryusuke , Celis Esteban 
Published: September 2005

AbstractPurpose: Human T-cell leukemia virus type I (HTLV-I) can cause an adult T-cell leukemia/lymphoma (ATLL). Because ATLL is a life-threatening lymphoproliferative disorder and is resistant to chemotherapy, the establishment and enhancement of T-cell immunity to HTLV-I through the development of therapeutic vaccines could be of value. Thus, the identification of HTLV-I epitopes for both CD8+ and CD4+ T cells should facilitate the development of effective vaccines. Although numerous HTLV-I epitopes for CTLs have been identified, few epitopes recognized by CD4+ helper T cells against this virus have been described.Experimental Design: Synthetic peptides prepared from several regions of the HTLV-I envelope (Env) sequence that were predicted to serve as helper T-cell epitopes were prepared with use of computer-based algorithms and tested for their capacity to trigger in vitro helper T-cell responses using lymphocytes from normal volunteers.Results: The results show that the HTLV-I–Env317–331, and HTLV-I–Env384–398-reactive helper T lymphocytes restricted by HLA-DQw6 and HLA-DR15, respectively, could recognize intact HTLV-I+ T-cell lymphoma cells and, as a consequence, secrete lymphokines. In addition, HTLV-I Env196–210-reactive helper T lymphocytes restricted by HLA-DR9 were able to directly kill HTLV-I+ lymphoma cells and recognize naturally processed antigen derived from killed HTLV-I+ lymphoma cells, which was presented to the helper T cells by autologous antigen-presenting cells.Conclusions: The present findings hold relevance for the design and optimization of T-cell epitope-based immunotherapy against HTLV-I–induced diseases such as ATLL.
Combination Therapy Enhances the Inhibition of Tumor Growth with the Fully Human Anti–Type 1 Insulin-Like Growth Factor Receptor Monoclonal Antibody CP-751,871
Authors: Cohen Bruce D. , Baker Deborah A. , Soderstrom Catherine , Tkalcevic George , Rossi Ann Marie , Miller Penny E. , Tengowski Mark W. , Wang Faye , Gualberto Antonio , Beebe Jean S. , Moyer James D. 
Published: September 2005

Abstract
Purpose: The insulin-like growth factor (IGF) signaling pathway is implicated in cellular mitogenesis, angiogenesis, tumor cell survival, and tumorigenesis. Inhibition of this pathway results in decreased cell growth, inhibition of tumor formation in animal models, and increased apoptosis in cells treated with cytotoxic chemotherapy. We generated and characterized a human monoclonal antibody that targeted the IGF receptor.
Experimental Design: By use of XenoMouse technology, we generated CP-751,871, a fully human IgG2 antibody with high affinity (Kd = 1.5 nmol/L) for human IGF-1R and evaluated its biological, pharmacologic, and antitumor properties.
Results: This antibody blocks binding of IGF-1 to its receptor (IC50 1.8 nmol/L), IGF-1-induced receptor autophosphorylation (IC50 0.42 nmol/L) and induced the down-regulation of IGF-1R in vitro and in tumor xenografts. The extent of IGF-1R down-regulation in vivo was proportional to CP-751,871 concentrations in the serum of tumor-bearing mice. Pharmacokinetic profiles in cynomolgus monkeys indicated a close to linear increase of exposure following i.v. dosing of antibody in the range of 3 to 100 mg/kg. CP-751,871 showed significant antitumor activity both as a single agent and in combination with Adriamycin, 5-fluorouracil, or tamoxifen in multiple tumor models. A biomarker assay was developed to establish the relationship between circulating antibody concentrations and down-regulation of IGF-1R in peripheral blood cells. The concentration of CP-751,871 required to down-regulate 50% of IGF-1R on peripheral blood cells was 0.3 nmol/L.
Conclusion: These data suggest that inhibition of the IGF cascade by use of this monoclonal antibody may be of clinical benefit in the treatment of human cancers.
Thrombopoietic Factors in Chronic Bone Marrow Failure States: The Platelet Problem Revisited
Authors: Kurzrock Razelle 
Published: September 2005

Abstract
Thrombocytopenia is a serious clinical problem in several different clinical settings. In chronic bone marrow failure states, which include aplastic anemia, myelodysplastic syndrome, and graft failure, the prolonged nature of thrombocytopenia often leads to alloimunization after repeated platelet transfusions, the consequence of which is a platelet-refractory state and enhanced risk of bleeding. Despite the introduction of several thrombopoietic factors into clinical trials, an effective way to alleviate thrombocytopenia has been elusive, and the problem in chronic bone marrow failure states has remained poorly addressed by clinical investigations. Even so, several studies by our group and others suggest that a subset of patients suffering from chronic bone marrow failure can respond to appropriate growth factor therapy. The temporal pace of response appears, however, to be much slower than that observed after administering growth factors which act on neutrophils. On the other hand, durable responses can be secured in some patients given thrombopoietic factors for long periods of time. Herein, we provide an overview of the clinical research investigations of thrombopoietic factors in chronic bone marrow failure, and the emerging insights these studies provide for understanding the process of thrombopoiesis and its therapy in this setting.
Vascular Endothelial Growth Factor-C Expression and Invasive Phenotype in Ovarian Carcinomas
Authors: Ueda Masatsugu , Hung Yao-Ching , Terai Yoshito , Kanda Koji , Kanemura Masanori , Futakuchi Hikari , Yamaguchi Hiroyuki , Akise Daisuke , Yasuda Masayuki , Ueki Minoru 
Published: September 2005

Abstract
Purpose: To investigate the biological correlation between vascular endothelial growth factor (VEGF)-C expression and invasive phenotype in ovarian carcinomas.
Experimental Design: Gene and protein expression levels of VEGF-C in 10 ovarian carcinoma cell lines were correlated with invasive activity of the cells. The correlation between immunohistochemical expression of VEGF-C and tumor aggressiveness in 73 ovarian carcinomas was also examined with respect to clinicopathologic features and patient outcome.
Results: VEGF-C gene and protein expression differed remarkably among the cell lines, and there was a statistical correlation among VEGF-C expression, in vitro invasive activity, and matrix metalloproteinase-2 (MMP-2) gene expression and its activity. Anti-VEGF-C and anti-MMP-2 antibodies inhibited the invasive activity of tumor cells. VEGF-C expression in clinical tissue samples was well correlated with clinical stages, retroperitoneal lymph node metastasis, MMP-2 expression, angiogenesis, lymphangiogenesis, and low apoptotic index (AI). The patients whose tumors had strong VEGF-C expression and low AI underwent a poorer prognosis than did those with weak VEGF-C expression and high AI.
Conclusion: VEGF-C expression is closely related to invasive phenotype and affects the patient's survival in ovarian carcinomas.
Effect of Chemokine Receptors CXCR4 and CCR7 on the Metastatic Behavior of Human Colorectal Cancer
Authors: Schimanski Carl C. , Schwald Stefan , Simiantonaki Nektaria , Jayasinghe Caren , Gönner Ursula , Wilsberg Vanessa , Junginger Theodor , Berger Martin R. , Galle Peter R. , Moehler Markus 
Published: September 2005

AbstractPurpose: The expression of chemokine receptors CXCR4 and CCR7 has been associated with tumor dissemination and poor prognosis in a limited number of tumor entities. However, no data are currently available on the impact of chemokine receptor expression on disease progression and prognosis in human colorectal cancer.Experimental Design: The expression of CXCR4 and CCR7 was evaluated in 96 patients with histologically confirmed colorectal cancers and in four colorectal cancer cell lines by immunohistochemical staining. Furthermore, cell migration assays were done with SW480, SW620, and LS174T cancer cells to confirm the effect of the CXCR4 ligand stromal cell–derived factor 1α on migration.Results: Human colorectal cancer specimens and cell lines displayed a CXCR4 and CCR7 expression with variable intensities. Interestingly, strong expression of CXCR4, but not of CCR7, was significantly associated with higher Union International Contre Cancer stages 3/4 (P = 0.0017), lymph node metastasis (P = 0.00375), and distant metastasis (P = 0.00003) and further correlated with a reduced 3-year survival rate (P = 0.1). Strong CXCR4 and CCR7 expression positively correlated with the location of the primary tumor in the rectum (P &lt; 0.01). Furthermore, activation of CXCR4-expressing cancer cells by stromal cell–derived factor 1α resulted in a significant increase of cell migration (P &lt; 0.014).Conclusion: Strong expression of CXCR4 by colorectal cancer cells is significantly associated with lymphatic and distant dissemination in patients with colorectal cancer as well as with cancer cell migration in vitro.
Inhibition of αvβ3 Integrin Survival Signaling Enhances Antiangiogenic and Antitumor Effects of Radiotherapy
Authors: Abdollahi Amir , Griggs David W. , Zieher Heike , Roth Alexandra , Lipson Kenneth E. , Saffrich Rainer , Gröne Hermann-Josef , Hallahan Dennis E. , Reisfeld Ralph A. , Debus Juergen , Niethammer Andreas G. , Huber Peter E. 
Published: September 2005

Abstract
The involvement of αvβ3 and αvβ5 integrins in angiogenesis and the use of integrin antagonists as effective antiangiogenic agents are documented. Radiotherapy is an important therapy option for cancer. It has been shown that ionizing radiation exerts primarily antiangiogenic effects in tumors but has also proangiogenic effects as the reaction of the tumor to protect its own vasculature from radiation damage. Here, we show that combined treatment with S247, an Arg-Gly-Glu peptidomimetic antagonist of αvβ3 integrin, and external beam radiotherapy are beneficial in local tumor therapy. We found that radiation up-regulates αvβ3 expression in endothelial cells and consecutively phosphorylates Akt, which may provide a tumor escape mechanism from radiation injury mediated by integrin survival signaling. In the presence of S247, the radiation-induced Akt phosphorylation is strongly inhibited. Our studies on endothelial cell proliferation, migration, tube formation, apoptosis, and clonogenic survival show that the radiosensitivity of endothelial cells is enhanced by the concurrent administration of the integrin antagonist. The in vitro data are successfully translated into human glioma (U87), epidermoid (A431), and prostate cancer (PC3) xenograft models growing s.c. on BALB/c-nu/nu mice. In vivo, the combination of S247 treatment and fractionated radiotherapy (5 × 2.5 Gy) leads to enhanced antiangiogenic and antitumor effects compared with either monotherapies. These results underline the importance of αvβ3 integrin when tumors protect their microvasculature from radiation-induced damage. The data also indicate that the combination of integrin antagonists and radiotherapy represents a rational approach in local cancer therapy.
Serum Mannan-Binding Lectin-Associated Serine Protease 2 Levels in Colorectal Cancer: Relation to Recurrence and Mortality
Authors: Ytting Henriette , Jarle Christensen Ib , Thiel Steffen , Jensenius Jens Christian , Nielsen Hans Jørgen 
Published: September 2005

Abstract
Purpose: Mannan-binding lectin-associated serine protease 2 (MASP-2) is a plasma protein involved in inflammatory processes. MASP-2 circulates in complex with the protein mannan-binding lectin (MBL) or ficolins, and is activated to recruit the complement system when MBL binds to its targets. The level of MASP-2 is genetically determined, and the aim of the present study was to evaluate the effect of MASP-2 levels on postoperative infection, recurrence and survival.
Experimental Design: MASP-2 concentrations were determined in serum from 605 patients collected before elective resection for primary colorectal cancer. The primary end points were postoperative infection, time to any recurrence, and time to death. The median time of follow-up was 7.9 years.
Results: MASP-2 levels were not correlated to postoperative infections (P = 0.49). High MASP-2 levels significantly correlated with recurrent cancer disease [P = 0.03; hazard ratio (HR) = 1.4; 95% confidence interval (CI), 1.0-2.0] and with poor survival (P = 0.0005; HR = 1.4; 95% CI, 1.2-1.7). Multivariate statistical analysis, including age, gender, Dukes' stage of disease, tumor localization, and postoperative pneumonia, showed that the MASP-2 level had an independent prognostic value in the patients (P = 0.0001; HR = 1.5; 95% CI, 1.2-1.8).
Conclusion: In the cohort of patients with colorectal cancer investigated, MASP-2 concentration in serum proved to be an independent prognostic marker with high MASP-2 levels predicting recurrence and poor survival. Postoperative infection could not be shown to be associated with MASP-2 levels.
Antitumor Efficacy of bcl-2 and c-myc Antisense Oligonucleotides in Combination with Cisplatin in Human Melanoma Xenografts: Relevance of the Administration Sequence
Authors: Zupi Gabriella , Scarsella Marco , Semple Sean C. , Mottolese Marcella , Natali Pier G. , Leonetti Carlo 
Published: September 2005

Abstract
Purpose: bcl-2 and c-myc oncogenes are frequently overexpressed in different human tumors, including melanoma. Here, we evaluate the combined efficacy of two antisense oligonucleotides targeting bcl-2 mRNA (ODN bcl-2) and c-myc mRNA (ODN c-myc) in combination with cis-diammine dichloroplatinum (cisplatin, DDP) on three human melanoma lines (LM, NG, and M20).
Experimental Design: Two different sequences were designed to treat tumor-bearing mice: in the first one, ODN bcl-2 at a dose of 0.2 mg/day ×4, followed by DDP given i.p. at a dose of 3.3 mg/kg/day ×3 and ODN c-myc i.v. at 0.5 mg/day ×7, whereas the other sequence consisted of ODN c-myc given as first agent followed by DDP and ODN bcl-2 at the same doses. Mice received three complete cycles of treatment in 1-week intervals.
Results: The treatment sequence with ODN bcl-2/DDP/ODN c-myc combination completely inhibited growth in NG tumor and induced a 35-day delay in LM tumor growth. In contrast, the M20 tumor growth was unaffected by the combination. A discrete amount of c-Myc and bcl-2 protein expression in both LM and NG tumors was detected, whereas no detectable levels of the two proteins were observed in M20 tumors. Compared with the other combination, the sequence (ODN bcl-2/DDP/ODN c-myc) produced the most effective results, producing a significant decrease in bcl-2 and c-Myc protein expression, which in turn significantly increased the survival of NG- and LM-bearing mice, with 4 mice out of 11 and 1 out of 7 mice being cured, respectively. Finally, this combination increased the apoptotic rate and produced an antiangiogenetic effect.
Conclusions: These results show that an antisense approach to the treatment of melanoma xenografts overexpressing either bcl-2 or c-myc oncogenes represents a successful strategy to improve the response to chemotherapy in melanoma, with particular attention to the treatment sequence.
Induction of an Antigen Cascade by Diversified Subcutaneous/Intratumoral Vaccination Is Associated with Antitumor Responses
Authors: Kudo-Saito Chie , Schlom Jeffrey , Hodge James W. 
Published: September 2005

Abstract
Purpose: Cancer vaccines targeting tumor-associated antigens are being investigated for the therapy of tumors. Numerous strategies, including the direct intratumoral (i.t.) vaccination route, have been examined. For tumors expressing carcinoembryonic antigen (CEA) as a model tumor-associated antigen, we previously designed poxviral vectors that contain the transgenes for CEA and a triad of T-cell costimulatory molecules, B7-1, intercellular adhesion molecule-1, (ICAM-1), and leukocyte function associated antigen-3 (LFA-3) (CEA/TRICOM). Two types of poxvirus vectors were developed: replication-competent recombinant vaccinia and replication-defective recombinant fowlpox. We have shown previously that a vaccine regimen composed of priming mice s.c. with recombinant vaccinia-CEA/TRICOM and boosting i.t. with recombinant fowlpox-CEA/TRICOM was superior to priming and boosting vaccinations using the conventional s.c. route in inducing T-cell responses specific for CEA. These studies also showed that CEA was needed to be present both in the vaccine and in the tumor for therapeutic effects.
Experimental Design: To determine specific immune responses associated with vaccination-mediated tumor regression, CEA-transgenic mice bearing CEA+ tumors were vaccinated with the CEA/TRICOM s.c./i.t. regimen, and T-cell immune responses were assessed.
Results: In CEA+ tumor-bearing mice vaccinated with the CEA/TRICOM s.c./i.t. regimen, T-cell responses could be detected not only to CEA encoded in vaccine vectors but also to other antigens expressed on the tumor itself: wild-type p53 and an endogenous retroviral epitope of gp70. Moreover, the magnitude of CD8+ T-cell immune responses to gp70 was far greater than that induced to CEA or p53. Finally, the predominant T-cell population infiltrating the regressing CEA+ tumor after therapy was specific for gp70.
Conclusion: These studies show that the breadth and magnitude of antitumor immune cascades to multiple antigens could be critical in the therapy of established tumors.
Phospho-Akt Expression Is Associated with a Favorable Outcome in Non–Small Cell Lung Cancer
Authors: Shah Amit , Swain William A. , Richardson Donna , Edwards John , Stewart Duncan J. , Richardson Catherine M. , Swinson Daniel E.B. , Patel Dipika , Jones J. Louise , O'Byrne Kenneth J. 
Published: September 2005

AbstractAkt, a Serine/Threonine protein kinase, mediates growth factor–associated cell survival. Constitutive activation of Akt (phosphorylated Akt, P-Akt) has been observed in several human cancers, including lung cancer and may be associated with poor prognosis and chemotherapy and radiotherapy resistance. The clinical relevance of P-Akt in non–small cell lung cancer (NSCLC) is not well described. In the present study, we examined 82 surgically resected snap-frozen and paraffin-embedded stage I to IIIA NSCLC samples for P-Akt and Akt by Western blotting and for P-Akt by immunohistochemistry. P-Akt protein levels above the median, measured using reproducible semiquantitative band densitometry, correlated with a favorable outcome (P = 0.007). Multivariate analysis identified P-Akt as a significant independent favorable prognostic factor (P = 0.004). Although associated with a favorable prognosis, high P-Akt levels correlated with high tumor grade (P = 0.02). Adenocarcinomas were associated with low P-Akt levels (P = 0.039). Akt was not associated with either outcome or clinicopathologic variables.Cytoplasmic (CP-Akt) and nuclear (NP-Akt) P-Akt tumor cell staining was detected in 96% and 42% of cases, respectively. Both CP-Akt and NP-Akt correlated with well-differentiated tumors (P = 0.008 and 0.017, respectively). NP-Akt also correlated with nodal metastases (P = 0.022) and squamous histology (P = 0.037).These results suggest P-Akt expression is a favorable prognostic factor in NSCLC. Immunolocalization of P-Akt, however, may be relevant as NP-Akt was associated with nodal metastases, a known poor prognostic feature in this disease. P-Akt may be a potential novel therapeutic target for the management of NSCLC.