bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resistance to Tyrosine Kinase Inhibition by Mutant Epidermal Growth Factor Receptor Variant III Contributes to the Neoplastic Phenotype of Glioblastoma Multiforme
Authors: Learn Chris A. , Hartzell Tristan L. , Wikstrand Carol J. , Archer Gary E. , Rich Jeremy N. , Friedman Allan H. , Friedman Henry S. , Bigner Darell D. , Sampson John H. 
Published: September 2005

Abstract
Purpose: We have reported previously that tumors expressing wild-type epidermal growth factor receptor (EGFR) in a murine model are sensitive to the EGFR tyrosine kinase inhibitor gefitinib, whereas tumors expressing mutant EGFR variant III (EGFRvIII) are resistant. Determination of how this differential inhibition occurs may be important to patient selection and treatment criteria, as well as the design of future therapeutics for glioblastoma multiforme.
Experimental Design: We have determined and quantified how treatment with gefitinib at commonly used, noncytotoxic doses affects neoplastic functions ascribed to EGFRvIII, including downstream signaling by Akt, DNA synthesis, and cellular invasion. In doing so, we have tested and compared a series of wild-type and mutant EGFRvIII-expressing fibroblast and glioblastoma cell lines in vitro after treatment with gefitinib.
Results: The results of these experiments demonstrate that short-term treatment with gefitinib (∼24 h) does not reduce phosphorylation of EGFRvIII, whereas EGFR phosphorylation is inhibited in a dose-dependent manner. However, after daily treatment with gefitinib, phosphorylation declines for EGFRvIII by day 3 and later. Nevertheless, after 7 days of daily treatment, cells that express and are dependent on EGFRvIII for tumorigenic growth are not effectively growth inhibited. This may be due in part to phosphorylation of Akt, which is inhibited in EGFR-expressing cells after treatment with gefitinib, but is unaffected in cells expressing EGFRvIII. Cell cycle analysis shows that nascent DNA synthesis in EGFR-expressing cells is inhibited in a dose-dependent manner by gefitinib, yet is unaffected in EGFRvIII-expressing cells with increasing dosage. Furthermore, cells expressing EGFRvIII demonstrate greater invasive capability with increasing gefitinib concentration when compared with cells expressing EGFR after treatment.
Conclusions: We conclude that the neoplastic phenotype of EGFRvIII is relatively resistant to gefitinib and requires higher doses, repeated dosing, and longer exposure to decrease receptor phosphorylation. However, this decrease does not effectively inhibit the biologically relevant processes of DNA synthesis, cellular growth, and invasion in cells expressing EGFRvIII.
Antitumor Effect of Intratumoral Administration of Bone Marrow-Derived Dendritic Cells Transduced with Wild-Type
p53
Gene
Authors: Murakami Takayoshi , Tokunaga Naoyuki , Waku Toshihiko , Gomi Shinya , Kagawa Shunsuke , Tanaka Noriaki , Fujiwara Toshiyoshi 
Published: September 2005

Abstract
Purpose: Dendritic cells (DCs) are attractive effectors for cancer immunotherapy because of their potential to function as professional antigen-presenting cells for initiating cellular immune responses. The tumor suppressor gene p53 is pivotal in the regulation of apoptosis, and ∼50% of human malignancies exhibit mutation and aberrant expression of p53. We investigated the antitumor effect of intratumoral administration of bone marrow-derived dendritic cells transduced with wild-type p53 gene.
Experimental Design: We examined whether intratumoral administration of DCs infected with recombinant adenovirus expressing murine wild-type p53 (Ad-mp53) could induce systemic antitumor responses against mutant p53-expressing tumors, highly immunogenic MethA, or weakly immunogenic MCA-207 implanted in syngeneic mice.
Results: Accumulation of wild-type p53 protein in bone marrow-derived murine DCs could be successfully achieved by Ad-mp53 infection. Treatment with intratumoral injection of Ad-mp53-transduced DCs caused a marked reduction in the in vivo growth of established MethA and MCA-207 tumors with massive cellular infiltrates. Administration of p53-expressing DCs suppressed the growth of both injected MCA-207 tumors and untreated distant MCA-207 tumors, but not unrelated Lewis lung carcinoma tumors, suggesting the augmentation of systemic immunogenicity against MCA-207 tumor cells. Moreover, intratumoral injection of p53-expressing DCs had a greater antitumor effect than did s.c. immunization.
Conclusions: Our results indicate that intratumoral administration of DCs expressing murine wild-type p53 leads to significant systemic immune responses and potent antitumor effects in mutant p53-expressing murine cancer models. These findings raise the possibility of using this strategy of intratumoral injection of p53-expressing DCs for human cancer treatment.
Soluble Type II Transforming Growth Factor-β Receptor Inhibits Established Murine Malignant Mesothelioma Tumor Growth by Augmenting Host Antitumor Immunity
Authors: Suzuki Eiji , Kapoor Veena , Cheung H.-Kam , Ling Leona E. , DeLong Peter A. , Kaiser Larry R. , Albelda Steven M. 
Published: September 2005

Abstract
Purpose: Transforming growth factor (TGF)-β blockade has been proposed as an anticancer therapy; however, understanding which tumor patients might benefit most from such therapy is crucial. An ideal target of such inhibitory therapy might be malignant mesothelioma (MM), a highly lethal, treatment-resistant malignancy of mesothelial cells of the pleura and peritoneum that produces large amounts of TGF-β. The purpose of this study was to explore the possible therapeutic utility of TGF-β blockade on MM.
Experimental Design: To evaluate this hypothesis, we tested the effects of a soluble TGF-β type II receptor (sTGF-βR) that specifically inhibits TGF-β1 and TGF-β3 in three different murine MM tumor models, AB12 and AC29 (which produce large amounts of TGF-β) and AB1 (which does not produce TGF-β).
Results: Tumor growth of both established AB12 and AC29 tumors was inhibited by sTGF-βR. In contrast, AB1 tumors showed little response to sTGF-βR. The mechanism of these antitumor effects was evaluated and determined to be primarily dependent on immune-mediated responses because (a) the antitumor effects were markedly diminished in severe combined immunodeficient mice or mice depleted of CD8+ T cells and (b) CD8+ T cells isolated from spleens of mice treated with sTGF-βR showed strong antitumor cytolytic effects, whereas CD8+ T cells isolated from spleens of tumor-bearing mice treated with of control IgG2a showed no antitumor cytolytic effects.
Conclusions: Our data suggest that TGF-β blockade of established TGF-β-secreting MM should be explored as a promising strategy to treat patients with MM and other tumors that produce TGF-β.
Mifepristone Induces Growth Arrest, Caspase Activation, and Apoptosis of Estrogen Receptor-Expressing, Antiestrogen-Resistant Breast Cancer Cells
Authors: Gaddy Virgil T. , Barrett John T. , Delk Jennifer N. , Kallab Andre M. , Porter Alan G. , Schoenlein Patricia V. 
Published: September 2005

Abstract
Purpose: A major clinical problem in the treatment of breast cancer is the inherent and acquired resistance to antiestrogen therapy. In this study, we sought to determine whether antiprogestin treatment, used as a monotherapy or in combination with antiestrogen therapy, induced growth arrest and active cell death in antiestrogen-resistant breast cancer cells.
Experimental Design: MCF-7 sublines were established from independent clonal isolations performed in the absence of drug selection and tested for their response to the antiestrogens 4-hydroxytamoxifen (4-OHT) and ICI 182,780 (fulvestrant), and the antiprogestin mifepristone (MIF). The cytostatic (growth arrest) effects of the hormones were assessed with proliferation assays, cell counting, flow cytometry, and a determination of the phosphorylation status of the retinoblastoma protein. The cytotoxic (apoptotic) effects were analyzed by assessing increases in caspase activity and cleavage of poly(ADP-ribose) polymerase.
Results: All of the clonally derived MCF-7 sublines expressed estrogen receptor and progesterone receptor but showed a wide range of antiestrogen sensitivity, including resistance to physiological levels of 4-OHT. Importantly, all of the clones were sensitive to the antiprogestin MIF, whether used as a monotherapy or in combination with 4-OHT. MIF induced retinoblastoma activation, G1 arrest, and apoptosis preceded by caspase activation.
Conclusions: We demonstrate that: (a) estrogen receptor+progesterone receptor+, 4-OHT-resistant clonal variants can be isolated from an MCF-7 cell line in the absence of antiestrogen selection; and (b) MIF and MIF plus 4-OHT combination therapy induces growth arrest and active cell death of the antiestrogen-resistant breast cancer cells. These preclinical findings show potential for a combined hormonal regimen of an antiestrogen and an antiprogestin to combat the emergence of antiestrogen-resistant breast cancer cells and, ultimately, improve the therapeutic index of antiestrogen therapy.
Loss of 14-3-3σ in Prostate Cancer and Its Precursors
Authors: Cheng Liang , Pan Chong-Xian , Zhang Jian-Ting , Zhang Shaobo , Kinch Michael S. , Li Lang , Baldridge Lee Ann , Wade Christopher , Hu Zhiqiang , Koch Michael O. , Ulbright Thomas M. , Eble John N. 
Published: September 2005

Abstract
Purpose: The 14-3-3 family proteins are highly conserved over many mammalian species. The σ isoform (also called HME-1 or stratifin) is expressed in epithelial cells. Loss of 14-3-3σ is associated with failure to arrest the cell cycle at the G2-M phase checkpoint after DNA damage that leads to increased G2-type chromosomal aberrations. The role of 14-3-3σ in prostatic carcinogenesis is uncertain.
Experimental Design: We studied one hundred and eleven specimens of invasive prostate adenocarcinoma with paired, adjacent high-grade prostatic intraepithelial neoplasia and normal prostate epithelium. Immunohistochemistry was used to detect the expression of 14-3-3σ. The findings were correlated with various clinical pathological parameters.
Results: 14-3-3σ is ubiquitously expressed at high levels in normal prostate epithelium. Its expression is significantly decreased in prostatic intraepithelial neoplasia and prostatic adenocarcinoma. Ninety percent of samples of prostatic intraepithelial neoplasia had no or low 14-3-3σ expression. Ninety-seven percent of invasive adenocarcinomas had no or low 14-3-3σ expression. In most specimens (90%), suppression of 14-3-3σ expression occurred during the development of prostatic intraepithelial neoplasia from normal epithelium.
Conclusions: Our data suggest that loss of 14-3-3σ contributes to the development of prostate adenocarcinoma. 14-3-3σ expression is significantly decreased during the progression of normal prostatic epithelium to prostatic intraepithelial neoplasia and invasive cancer.
pRb2/p130, Vascular Endothelial Growth Factor, p27(KIP1), and Proliferating Cell Nuclear Antigen Expression in Hepatocellular Carcinoma
Authors: Claudio Pier Paolo , Russo Giuseppe , Kumar Christine A. C. Y. , Minimo Corrado , Farina Antonio , Tutton Steve , Nuzzo Gennaro , Giuliante Felice , Angeloni Giulia , Maria Vellone , Vecchio Fabio Maria , Campli Cristiana Di , Giordano Antonio 
Published: September 2005

Abstract
Hepatocarcinoma (HCC) is the fifth most common cancer, with more than one million fatalities occurring annually worldwide. Multiple risk factors are associated with HCC disease etiology, the highest incidence being in patients with chronic hepatitis B virus and hepatitis C virus, although other factors such as genetic makeup and environmental exposure are involved. Multiple genetic alterations including the activation of oncogenes and inactivation of tumor suppressor genes are required for malignancy in human cancers and are correlated with increased stages of carcinogenesis and further tumor progression. In this study of 21 HCC patients, we analyzed pRb2/p130, vascular endothelial growth factor (VEGF), p27(KIP1), and proliferating cell nuclear antigen as potential HCC molecular biomarkers. In our sample set, we found that p27(KIP1) was absent. Univariate survival analysis showed that proliferating cell nuclear antigen expression (diffuse staining &gt;50% of positive cells in tumor) was confirmed as a significant HCC prognostic biomarker for determining patient survival agreeing with previous studies (P = 0.0126, log-rank test). Lower pRb2/p130 expression was associated to a borderline P value of inverse correlation with tumor malignancy and to a positive correlation with respect to the time from HCC diagnosis (Spearman coefficient = 0.568; P &lt; 0.05). Conversely, higher VEGF expression was associated with a poor survival (P = 0.0257, log-rank test). We demonstrate for the first time that pRb2/p130 is inversely correlated with VEGF expression and tumor aggressiveness (P &lt; 0.05) in p27(KIP1)-negative HCC patients. pRb2/p130 and VEGF expression are independent from tumor staging, suggesting their possible role as independent prognostic molecular biomarkers in HCC. Furthermore, we have evidence that VEGF together with pRb2/p130 may act as new HCC biomarkers in a p27(KIP1)-independent manner. Additional studies with larger numbers of patient data would allow the use of multivariable techniques and would be able to further identify patients with poorer survival.
Phase II Study of the Flk-1 Tyrosine Kinase Inhibitor SU5416 in Advanced Melanoma
Authors: Peterson Amy C. , Swiger Susan , Stadler Walter M. , Medved Milica , Karczmar Greg , Gajewski Thomas F. 
Published: September 2005

Abstract
Purpose: Vascular endothelial growth factor (VEGF) expression is prognostic in melanoma, and the activity of VEGF is mediated in part through the receptor tyrosine kinase Flk-1. A Phase II study of SU5416, a preferential inhibitor of Flk-1, was carried out in patients with metastatic melanoma to determine clinical response, tolerability, and changes in tumor vascular perfusion.
Experimental Design: Patients with documented progressive disease and ≤1 prior therapy were eligible. Central nervous system metastases were allowed if stable off medication. SU5416 (145 mg/m2) was administered via a central catheter twice weekly for 8 weeks. Premedication with dexamethasone, diphenhydramine, and a H2 blocker was required because of the Cremophor vehicle. Tumor vascular perfusion was assessed before treatment and during week 8 by dynamic contrast magnetic resonance imaging, and plasma was analyzed for VEGF.
Results: Thirty-one patients were enrolled. Two-thirds had received prior therapy, 21 had visceral metastasis, and 14 had an elevated lactate dehydrogenase. Mean absolute lymphocyte counts were decreased (P = 0.002), and glucose levels were increased (P = 0.001) posttherapy, presumably because of steroid premedication. Four vascular adverse events were observed. Of 26 evaluable patients, 1 experienced a partial response, 1 had stable disease, and 5 had a mixed response. Dynamic contrast magnetic resonance imaging in 5 evaluable patients showed decreased tumor perfusion at week 8 (P = 0.024), and plasma VEGF levels were elevated compared with pretherapy (P = 0.008).
Conclusions: SU5146 appears to be relatively well tolerated in this population. Although the modest clinical activity and potential effects on tumor vascularity may support additional exploration of VEGF as a target in melanoma, effects from steroid premedication limit further investigation of this agent.
Data from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trial
Authors: Buzdar Aman U. 
Published: September 2005

Abstract
The third-generation aromatase inhibitors (AIs) have improved efficacy and safety versus tamoxifen for treatment of advanced breast cancer. Currently, anastrozole is the only third-generation AI with adjuvant therapy data in postmenopausal women. Initial and updated results from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial (median follow-up, 47 months) confirm it to be more effective than tamoxifen for disease-free survival with several important tolerability benefits. As a result, there has been much debate about whether or not anastrozole should be used routinely to treat postmenopausal women with early breast cancer. In its review, the American Society of Clinical Oncology Health Services Research Committee agreed that the updated ATAC analyses provided a greater level of assurance, in terms of both toxicity and efficacy, for use of anastrozole in the adjuvant setting. However, pending 5-year data from ATAC and other trials of adjuvant AI use, adjuvant anastrozole was recommended by American Society of Clinical Oncology Health Research Committee for use only under certain circumstances, with 5 years of tamoxifen remaining the standard. Anastrozole should be the preferred AI in this setting; data from the ATAC trial should not be extrapolated to other members of the class. Despite this conservative recommendation, the overall risk:benefit profile from the ATAC trial favors anastrozole, and it is expected that a more favorable efficacy and adverse effect profile will be maintained. Anastrozole should, therefore, now be considered a valid alternative option to tamoxifen for adjuvant hormonal treatment in all postmenopausal women with hormone receptor-positive early breast cancer.
Gastrin-Induced Cyclooxygenase-2 Expression in Barrett’s Carcinogenesis
Authors: Abdalla Salem I. , Lao-Sirieix Pierre , Novelli Marco R. , Lovat Laurence B. , Sanderson Ian R. , Fitzgerald Rebecca C. 
Published: September 2005

AbstractPurpose: Cyclooxygenase (COX)-2 has been causally implicated in carcinogenesis. The evidence for increased COX-2 in the malignant progression of Barrett’s esophagus is contradictory. We hypothesize that COX-2 expression may be causally affected by the gastrin status via the cholecystokinin 2 (CCK2) receptor.Experimental Design: COX-2 and prostaglandin E2 expression were evaluated by Western blotting and enzyme-linked immune assay in samples of squamous esophagus, Barrett’s esophagus with varying degrees of dysplasia to adenocarcinoma, and normal duodenum. Differentiation status was evaluated by histopathology and villin expression. A longitudinal case-control study compared COX-2 in patients who progressed to adenocarcinoma with nonprogressors matched for age and length of follow-up. Messenger RNA levels of gastrin and CCK2 receptor in biopsies and cell lines were evaluated by reverse transcription-PCR, and in vitro gastrin stimulation was conducted with and without inhibitors for CCK2 (YM022) and COX-2 (NS-398). Cell proliferation was evaluated using minichromosome maintenance protein 2 (Mcm2) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays.Results: COX-2 expression is significantly increased in Barrett’s esophagus before dysplasia development. Expression is highly variable within Barrett’s dysplasia and adenocarcinoma samples independent of differentiation status. In a longitudinal case-control study, the expression levels within patients increased over time, regardless of the degree of malignant progression. Biopsies from nondysplastic Barrett’s esophagus expressed increased gastrin mRNA levels compared with other biopsies. Gastrin significantly induced COX-2, prostaglandin E2, and cell proliferation in biopsies and cell lines. Gastrin-induced proliferation can be inhibited by YM022 and NS-398.Conclusions: COX-2 is up-regulated early in the Barrett’s metaplasia sequence. During carcinogenesis, gastrin is a significant determinant of COX-2 activity levels via the CCK2 receptor.
Fibrinogen-Coated Droplets of Olive Oil for Delivery of Docetaxel to a Fibrin(ogen)-Rich Ascites Form of a Murine Mammary Tumor
Authors: Einhaus Charity M. , Retzinger Andrew C. , Perrotta Andre O. , Dentler Michael D. , Jakate Abhijeet S. , Desai Pankaj B. , Retzinger Gregory S. 
Published: September 2005

AbstractMicronized droplets of olive oil loaded with docetaxel and coated with functional fibrinogen were administered intraperitoneally to mice bearing the fibrin(ogen)-rich ascites form of the TA3/St mammary tumor. When compared with docetaxel administered intraperitoneally as its commercial formulation (i.e., Taxotere), docetaxel-loaded oil droplets coated with murine fibrinogen prolonged the median survival time of tumor-bearing mice from 14.5 to 29.5 days. Drug-free oil droplets provided no therapeutic benefit. Significantly more docetaxel was associated with tumor cells 24 and 48 hours after administration of the drug in fibrinogen-coated oil droplets than after its administration as Taxotere. Consistent with a role for thrombin in the retention of fibrinogen-coated oil droplets within the tumor microenvironment, hirudin significantly reduced the association of tumor cells with docetaxel delivered in fibrinogen-coated oil droplets and, at the same time, reduced the therapeutic efficacy of the droplets to that of Taxotere. Importantly, fibrinogen-coated oil droplets formed rosettes with tumor cells in vivo, a process prevented by hirudin. Although mice treated with oil droplets developed antifibrinogen antibodies, those antibodies seemed to be inconsequential. Taken together, our results and observations indicate fibrinogen-coated oil droplets markedly improve the therapeutic efficacy of docetaxel for the treatment of a mammary tumor grown in ascites form, a consequence of thrombin-mediated retention of the drug-loaded droplets within the tumor microenvironment.
Patterns of Chromosomal Alterations in Breast Ductal Carcinoma
In situ
Authors: Hwang E. Shelley , DeVries Sandy , Chew Karen L. , Moore Dan H. , Kerlikowske Karla , Thor Ann , Ljung Britt-Marie , Waldman Frederic M. 
Published: September 2005

Abstract
Purpose: Ductal carcinoma in situ (DCIS) is thought to be a nonobligate precursor of invasive cancer. Genomic changes specific to pure DCIS versus invasive cancer, as well as alterations unique to individual DCIS subtypes, have not been fully defined.
Experimental Design: Chromosomal copy number alterations were examined by comparative genomic hybridization in 34 cases of pure DCIS and compared with 12 cases of paired synchronous DCIS and invasive ductal cancer, as well as to 146 additional cases of invasive breast cancer of ductal or lobular histology. Genomic differences between high-grade and low/intermediate-grade DCIS, as well as between pure DCIS and invasive cancer, were identified.
Results: Pure DCIS showed almost the same degree of chromosomal instability as invasive ductal cancers. A higher proportion of low/intermediate-grade versus high-grade DCIS had loss of 16q (65 versus 12%, respectively; P = 0.002). When compared with lower grade DCIS, high-grade DCIS exhibited more frequent gain of 17q (65 versus 41%; P = 0.15) and higher frequency loss of 8p (77 versus 41%; P = 0.04). Chromosomal alterations in those cases with synchronous DCIS and invasive ductal cancer showed a high degree of shared changes within the two components.
Conclusions: DCIS is genetically advanced, showing a similar degree of chromosomal alterations as invasive ductal cancer. The pattern of alterations differed between high- and low/intermediate-grade DCIS, supporting a model in which different histological grades of DCIS are associated with distinct genomic changes. These regions of chromosomal alterations may be potential targets for treatment and/or markers of prognosis.