bluuebunny/crossref_metadata_2025_split huggingface dataset:
Different Activation of Mitogen-Activated Protein Kinase and Akt Signaling Is Associated with Aggressive Phenotype of Human Meningiomas
Authors: Mawrin Christian , Sasse Tina , Kirches Elmar , Kropf Siegfried , Schneider Thomas , Grimm Christoph , Pambor Claudia , Vorwerk Christian K. , Firsching Raimund , Lendeckel Uwe , Dietzmann Knut 
Published: September 2005

Abstract
Purpose: Activation of intracellular signaling cascades has been implicated in the growth control of benign meningiomas, but their role for meningioma progression and outcome is unknown. Here we determined the expression and function of proteins involved in mitogen-activated protein kinase (MAPK) and phosphinositol-3 kinase (PI3K)/Akt signaling in benign, atypical, and malignant meningiomas and studied their association with clinicopathologic data including meningioma recurrence.
Experimental Design: Expression of various MAPK and PI3K signaling proteins was determined in 70 primary meningiomas and, if present, in recurrent tumors by immunohistochemistry and Western blotting. The expression patterns in primary and recurrent tumors were related to clinical data. The effect of MAPK and PI3K pathway inhibition on cell proliferation and apoptosis was determined using a primary malignant meningioma cell culture.
Results: Atypical and malignant meningiomas showed higher levels of phospho-Akt compared with benign tumors, and their proliferation could be inhibited by PI3K blocking using wortmannin. PI3K inhibition did not induce apoptosis in malignant meningioma cells. In contrast, expression of phospho-Raf and phospho-MAPK was decreased in aggressive meningiomas compared with benign tumors, but MAPK inhibition by PD98059 resulted in tumor cell apoptosis and decreased proliferation. Reduced MAPK activation was associated with meningioma recurrence, and PI3K activation was associated with poor preclinical condition and brain invasion of malignant meningiomas.
Conclusions: Both MAPK and PI3K/Akt pathways are activated at different levels in benign and malignant meningiomas. Activation of PI3K/Akt signaling contributes to the aggressive behavior of malignant meningiomas, whereas MAPK activation is involved in both proliferation and apoptosis of malignant meningiomas.
Chemopreventive and Therapeutic Efficacy of Orally Active Tyrosine Kinase Inhibitors in a Transgenic Mouse Model of Gallbladder Carcinoma
Authors: Kiguchi Kaoru , Ruffino Lynnsie , Kawamoto Toru , Ajiki Tetsuo , DiGiovanni John 
Published: September 2005

Abstract
Biliary tract cancer (BTC) is the second most common primary hepatobiliary cancer after hepatocellular cancer. At the time of diagnosis, most BTC are at an advanced stage and are unresectable. There is presently no effective curative treatment of the advanced disease nor is there any effective clinical therapy that will prevent the development of BTC. All of these factors render gallbladder cancer nearly incurable with a poor survival rate. The aim of our study was to provide a better understanding of the mechanisms involved in the development of gallbladder carcinoma as the advancement of more effective treatment options would significantly improve prognosis. In the present study, we examined the effect of gefitinib, a selective epidermal growth factor receptor/tyrosine kinase inhibitor (EGFR/TKI), on the development of gallbladder carcinoma in BK5.erbB2 mice. In addition, we examined the effect of another quinazoline derivative, GW2974, which is able to block the activation of both the EGFR and erbB2, in this model. Animals were treated with either 400 ppm gefitinib or 200 ppm GW2974 as a supplement in the diet using either a chemopreventive or therapeutic protocol. The results show that both compounds were potent chemopreventive and therapeutic agents in this mouse model of human BTC. The results also suggest that activation of the EGFR plays an important role in development of BTC in this model and that targeting both the EGFR and erbB2 may be an effective strategy for treatment of this disease.
Down-Regulation and Growth Inhibitory Role of C/EBPα in Breast Cancer
Authors: Gery Sigal , Tanosaki Sakae , Bose Shikha , Bose Namrata , Vadgama Jay , Koeffler H. Phillip 
Published: September 2005

Abstract
Purpose: CCAAT/enhancer binding proteins (C/EBP) are a family of transcription factors that regulate proliferation and differentiation in a variety of tissues. The purpose of this study was to explore the possibility that C/EBPα is involved in breast cancer.
Experimental Design: We quantified C/EBPα mRNA expression levels in 24 primary breast tumors, 16 normal breast samples, and 8 breast cancer cell lines using quantitative real-time reverse transcription-PCR assay. C/EBPα protein levels were further determined by immunohistochemical analysis. To examine the consequence of C/EPBα expression in breast cancer, we stably transfected an inducible C/EPBα expression vector into three breast cancer cell lines.
Results: Low expression of C/EBPα mRNA was found in 83% of primary breast cancer samples. Immunohistochemical study further showed either a markedly reduced or undetectable expression of C/EBPα protein in 30% of breast cancer specimens. The other 70% of breast cancers had C/EBPα expression in both the cytoplasm and nucleus; in control, C/EBPα was localized to the nucleus in the normal ductal cells. C/EBPα expression was associated with estrogen- and progesterone receptor–negative status. Induction of C/EBPα expression in these cell lines resulted in growth inhibition accompanied by G0-G1 cell cycle arrest and reduced anchorage-independent cell growth. C/EBPα expression was associated with down-regulation of c-myc and up-regulation of p21, PPARγ, and the breast epithelial differentiation marker, maspin.
Conclusions: These results suggest that reduced expression of C/EBPα may play a role in the development and/or progression of breast cancer.
Combination Treatment with Erlotinib and Pertuzumab against Human Tumor Xenografts Is Superior to Monotherapy
Authors: Friess Thomas , Scheuer Werner , Hasmann Max 
Published: September 2005

Abstract
In many solid tumors, overexpression of human epidermal growth factor receptors (e.g., HER1/EGFR and HER2) correlates with poor prognosis. Erlotinib (Tarceva) is a potent HER1/EGFR tyrosine kinase inhibitor. Pertuzumab (Omnitarg), a novel HER2-specific, recombinant, humanized monoclonal antibody, prevents heterodimerization of HER2 with other HERs. Both mechanisms disrupt signaling pathways, resulting in tumor growth inhibition. We evaluated whether inhibition of both mechanisms is superior to monotherapy in tumor cell lines expressing different HER levels. Human non–small cell lung cancer (NSCLC) cells (Calu-3: HER1/EGFR 0+, HER2 3+; QG56: HER1/EGFR 2-3+, HER2 0+) and breast cancer cells (KPL-4: HER1/EGFR 2-3+, HER2 3+) were implanted into BALB/c nu/nu mice and severe combined immunodeficient beige mice, respectively. Tumor-bearing mice (n = 12 or 15 per group) were treated with vehicle (Captisol or buffer), erlotinib (orally, 50 mg/kg/d), pertuzumab (i.p. 6 mg/kg/wk with a 2-fold loading dose), or erlotinib and pertuzumab for 20 (QG56), 27 (KPL-4), or 49 (Calu-3) days. Drug monotherapy had antitumor activity in all models. Tumor volume treatment-to-control ratios (TCR) with erlotinib were 0.36 (Calu-3), 0.79 (QG56), and 0.51 (KPL-4). Pertuzumab TCR values were 0.42, 0.51, and 0.64 in Calu-3, QG56, and KPL-4 models, respectively. Combination treatment resulted in additive (QG56: TCR 0.39; KPL-4: TCR 0.38) or greater than additive (Calu-3: TCR 0.12) antitumor activity. Serum tumor markers for NSCLC (Cyfra 21.1) and breast cancer (soluble HER2) were markedly inhibited by combination treatment (80-97% in Calu-3 and QG56; 92% in KPL-4), correlating with decreased tumor volume. Overall, erlotinib and pertuzumab are active against various human xenograft models, independently of HER1/EGFR or HER2 expression. A combination of these HER-targeted agents resulted in additive or greater than additive antitumor activity.
Early Antiangiogenic Activity of SU11248 Evaluated In vivo by Dynamic Contrast-Enhanced Magnetic Resonance Imaging in an Experimental Model of Colon Carcinoma
Authors: Marzola Pasquina , Degrassi Anna , Calderan Laura , Farace Paolo , Nicolato Elena , Crescimanno Caterina , Sandri Marco , Giusti Anna , Pesenti Enrico , Terron Andrea , Sbarbati Andrea , Osculati Francesco 
Published: September 2005

Abstract
Purpose: To compare two dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) techniques in terms of their ability in assessing the early antiangiogenic effect of SU11248, a novel selective multitargeted tyrosine kinase inhibitor, that exhibits direct antitumor and antiangiogenic activity via inhibition of the receptor tyrosine kinases platelet-derived growth factor receptor, vascular endothelial growth factor receptor, KIT, and FLT3.
Experimental Design: A s.c. tumor model of HT29 human colon carcinoma in athymic mice was used. Two DCE-MRI techniques were used based, respectively, on macromolecular [Gd-diethylenetriaminepentaacetic acid (DTPA)-albumin] and low molecular weight (Gd-DTPA) contrast agents. The first technique provided a quantitative measurement of transendothelial permeability and fractional plasma volume, accepted surrogate markers of tumor angiogenesis. With the second technique, we quantified the initial area under the concentration-time curve, which gives information related to tumor perfusion and vascular permeability. Experiments were done before and 24 hours after a single dose administration of SU11248.
Results: The early antiangiogenic effect of SU11248 was detected by DCE-MRI with macromolecular contrast agent as a 42% decrease in vascular permeability measured in the tumor rim. The effect was also detected by DCE-MRI done with Gd-DTPA as a 31% decrease in the initial area under the concentration-time curve. Histologic slices showed a statistically significant difference in mean vessel density between the treated and control groups.
Conclusions: The early antiangiogenic activity of SU11248 was detected in vivo by DCE-MRI techniques using either macromolecular or low molecular weight contrast agents. Because DCE-MRI techniques with low molecular weight contrast agents can be used in clinical studies, these results could be relevant for the design of clinical trials based on new paradigms.
Gene Expression Profiles Associated with Response to Chemotherapy in Epithelial Ovarian Cancers
Authors: Jazaeri Amir A. , Awtrey Christopher S. , Chandramouli Gadisetti V.R. , Chuang Yao Eric , Khan Javed , Sotiriou Christos , Aprelikova Olga , Yee Cindy J. , Zorn Kristin K. , Birrer Michael J. , Barrett J. Carl , Boyd Jeff 
Published: September 2005

Abstract
Purpose: The goal of this study was to determine whether distinct gene expression profiles are associated with intrinsic and/or acquired chemoresistance in epithelial ovarian carcinoma.
Experimental Design: Gene expression profiles were generated from 21 primary chemosensitive tumors and 24 primary chemoresistant tumors using cDNA-based microarrays. Gene expression profiles of both groups of primary tumors were then compared with those of 15 ovarian carcinomas obtained following platinum-based chemotherapy (“postchemotherapy” tumors). A theme discovery tool was used to identify functional categories of genes involved in drug resistance.
Results: Comparison of primary chemosensitive and chemoresistant tumors revealed differential expression of 85 genes (P &lt; 0.001). Comparison of gene expression profiles of primary chemosensitive tumors and postchemotherapy tumors revealed more robust differences with 760 genes differentiating the two groups (P &lt; 0.001). In contrast, only 230 genes were differentially expressed between primary chemoresistant and postchemotherapy groups (P &lt; 0.001). Common to both gene lists were 178 genes representing transcripts differentially expressed between postchemotherapy tumors and all primary tumors irrespective of intrinsic chemosensitivity. The gene expression profile of postchemotherapy tumors compared with that of primary tumors revealed statistically significant overrepresentation of genes encoding extracellular matrix–related proteins.
Conclusions: These data show that gene expression profiling can discriminate primary chemoresistant from primary chemosensitive ovarian cancers. Gene expression profiles were also identified that correlate with states of intrinsic and acquired chemoresistance and that represent targets for future investigation and potential therapeutic interventions.
Characterization of a R115777-Resistant Human Multiple Myeloma Cell Line with Cross-Resistance to PS-341
Authors: Buzzeo Robert , Enkemann Steven , Nimmanapalli Rama , Alsina Melissa , Lichtenheld Mathias G. , Dalton William S. , Beaupre Darrin M. 
Published: September 2005

Abstract
The farnesyl transferase inhibitor R115777 has been found to have clinical activity in diverse hematopoietic tumors. Clinical efficacy, however, does not correlate with Ras mutation status or inhibition of farnesyl transferase. To further elucidate the mechanisms by which R115777 induces apoptosis and to investigate drug resistance, we have identified and characterized a R115777-resistant human myeloma cell line. 8226/R5 cells were found to be at least 50 times more resistant to R115777 compared with the parent cell line 8226/S. K-Ras remained prenylated in both resistant and sensitive cells after R115777 treatment; however, HDJ-2 farnesylation was inhibited in both lines, implying that farnesyl transferase (the drug target) has not been mutated. Whereas many 8226 lines that acquire drug resistance have elevated expression of P-glycoprotein, we found that P-glycoprotein expression is not increased in the 8226/R5 line and intracellular accumulation of R115777 was not reduced. In fact, 8226/R5 cells were insensitive to a diverse group of antitumor agents including PS-341, and multidrug resistance did not correlate with the expression of heat shock proteins. Comparison of gene expression profiles between resistant and sensitive cells revealed expression changes in several genes involved in myeloma survival and drug resistance. Future experiments will attempt to identify genes that are directly linked to the resistant phenotype. Identification of molecules associated with R115777 and PS-341 resistance is clinically relevant because both compounds are being tested in solid tumors and hematopoietic malignancies.
Curtailing the High Rate of Late-Stage Attrition of Investigational Therapeutics Against Unprecedented Targets in Patients with Lung and Other Malignancies
Authors: Rowinsky Eric K. 
Published: September 2005

Abstract
A greater understanding of the pathogenesis and biology of cancer coupled with major advances in biotechnology has resulted in the identification of rationally designed, target-based (RDTB) anticancer therapeutics, ushering in new therapeutic opportunities and high expectations for the future as well as developmental challenges. Because these agents appear to principally target malignant cells, it is expected that they will produce less toxicity at clinically effective doses than nonspecific cytotoxic agents, but their target requirements are likely to be much more stringent. The innate complexity of the networks that contain elements targeted by these agents also decreases the probability that any single therapeutic manipulation will result in robust clinical activity and success when used alone, particularly in patients with solid malignancies that have multiple relevant signaling aberrations. In contrast, proof of principle and robust antitumor activity may be most efficiently demonstrated in nonrandomized evaluations involving tumors that are principally driven by aberrations of the specific target. The predominant therapeutic manifestation of RDTB agents in preclinical studies is due to decreased tumor growth rates and will likely be similar in the clinic; however, such manifestations are not readily detectable and quantifiable using nonrandomized clinical evaluations. To curtail the increasing rate of late-stage attrition of RDTB agents, which, if maintained, will stymie progress in cancer therapy, the design of initial nonrandomized evaluations, particularly the selection of tumors and patients, must be guided by the principal biological features of the agents. Next, evaluations, some of which must be randomized, can be performed in a wide range of tumor types, depending on the presence and relevance of the target. To validate the concept of RDTB therapeutics and to realize their full potential, radically different development, evaluation, and regulatory paradigms must be adopted.
Farnesyl Transferase Inhibitors for Patients with Lung Cancer
Authors: Johnson Bruce E. , Heymach John V. 
Published: September 2005

Abstract
The ras family of genes have been identified as potential targets for therapeutic intervention because of somatic mutations in different human cancers. They are mutated in non-small cell lung cancer (NSCLC) ∼20% of the time. The enzyme farnesyl transferase is involved in posttranslational modification of the ras proteins by covalently linking a farnesyl group to the ras protein. This permits the ras protein to be translocated to the surface membrane, allowing the protein to be involved in signaling for increased proliferation and inhibition of apoptosis. The class of farnesyl transferase inhibitors is designed to block farnesylation and prevent the mature ras signaling and thus inhibit cell proliferation and facilitate apoptosis. Multiple agents that inhibit farnesylation have been developed, and two farnesyl transferase inhibitors have been tested in patients with lung cancer in three Phase II trials. R115777 has been studied in patients with NSCLC and in patients with relapsed small cell lung cancer (SCLC) after chemotherapy. There has been a single trial of L-778,123 in patients with untreated NSCLC. No objective tumor responses in patients with stage IIIB/IV NSCLC were seen in these studies. There were also no objective responses among the 22 patients with relapsed SCLC treated with R115777. The median survival for the 44 patients with NSCLC treated with R115777 was ∼8 months, whereas it was 11 months for the 23 patients treated with L-778,123. R115777 and L-778,123 were well tolerated in these studies but showed no significant activity as single-agent therapy in relapsed SCLC or untreated NSLC.
Skeletal Complications in Patients with Bone Metastases from Renal Cell Carcinoma and Therapeutic Benefits of Zoledronic Acid
Authors: Lipton Allan , Colombo-Berra Alejandro , Bukowski Ronald M. , Rosen Lee , Zheng Ming , Urbanowitz Gladys 
Published: September 2005

Abstract
Bone metastases in patients with renal cell carcinoma are associated with a high risk of skeletal complications. Therefore, a subset analysis of a larger clinical trial was performed to determine the efficacy of zoledronic acid in renal cell carcinoma patients. Patients with bone metastases from solid tumors other than breast or prostate cancer (n = 773) were randomized to receive zoledronic acid or placebo via 15-minute infusion every 3 weeks for 9 months. Patients were monitored for skeletal-related events, which were defined as pathological fracture, spinal cord compression, radiotherapy, or surgery to bone. Among the subset of 74 patients with renal cell carcinoma, 46 patients were treated with 4 mg of zoledronic acid or placebo. Significantly fewer patients treated with 4 mg zoledronic acid had a skeletal-related event (37% versus 74% for placebo, P = 0.015), and zoledronic acid significantly prolonged the time to first skeletal-related event (median not reached at 9 months versus 72 days for placebo; P = 0.006). Zoledronic acid significantly reduced the annual incidence of skeletal-related events by ∼21% (mean 2.68 versus 3.38 events per year for placebo, P = 0.014) and significantly reduced the risk of developing a skeletal-related event by 61% compared with placebo (risk ratio = 0.394, P = 0.008) by multiple event analysis. Median time to progression of bone lesions was also significantly extended with zoledronic acid treatment (P = 0.014). Zoledronic acid is the first bisphosphonate to significantly reduce skeletal morbidity and significantly prolong time to bone lesion progression in patients with bone metastases from renal cell carcinoma.
Therapeutic Options for Variant Renal Cancer
Authors: Stadler Walter M. 
Published: September 2005

Abstract
Variant or nonclear cell renal cell cancer is a rare disease constituting only ∼5% to 8% of the metastatic renal cell cancer population. Pathological criteria for the three main variant subtypes, papillary, chromophobe, and collecting duct, have been specified. Nonetheless, there may be subtypes within these variants, many poorly differentiated tumors cannot be reliably classified, and expertise in recognizing specific subtypes is not widespread. Expression analysis and other molecular techniques are beginning to clarify and standardize the pathological classification scheme. Because these classifications are relatively new and the number of patients with any one subtype is limited, little is known about appropriate therapies for patients with metastatic disease. Retrospective series strongly suggest that immunotherapy is not effective in any nonclear cell subtype. Case reports suggest that cytotoxic chemotherapy used for transitional cell cancers may be helpful in patients with collecting duct cancers. A central registry of patients with variant renal cell cancer should be created in which response to various therapies is recorded. Such a registry could provide support for a more formal multi-institutional study investigating a specific drug or regimen.
Celecoxib But Not Rofecoxib Inhibits the Growth of Transformed Cells
in Vitro
Authors: Kazanov Diana , Dvory-Sobol Hadas , Pick Marjorie , Liberman Eliezer , Strier Ludmila , Choen-Noyman Efrat , Deutsch Varda , Kunik Talya , Arber Nadir 
Published: September 2005

Abstract
Purpose: Nonsteroidal anti-inflammatory drugs reduce the risk of colorectal cancer. The cyclooxygenase (COX) pathway of arachidonic acid metabolism is an important target for nonsteroidal anti-inflammatory drugs. Increased expression of COX-2 was recently shown to be an important step in the multistep process of colorectal cancer carcinogenesis. The new COX-2-specific inhibitors offer the benefit of cancer protection without the gastrointestinal toxicity reported for the old drugs. The purpose of this study was to compare the growth effects of two specific COX-2 inhibitors, celecoxib (Pfizer, Inc., New York, NY), and rofecoxib (Merck, White House Station, NJ) in normal and transformed enterocytes.
Experimental Design: Cultures of normal rat intestinal epithelial cell line, IEC-18, vector control cells, c-K-ras, c-K-ras-bak, and antisense-bak derivatives were treated with different dosages of celecoxib (0–60 μm) and rofecoxib (0–20 μm). Cell cycle analysis and apoptosis were assessed by fluorescence-activated cell sorting analysis. Protein expression was assessed by Western blot analysis and caspases 3 and 8 activities by ELISA.
Results: Celecoxib inhibited cell growth and induced apoptosis in a time- and dose-dependent manner. IEC18 parental cells were two to four times more resistant to celecoxib than ras, ras-bak, and antisense bak transformed cells that overexpress the COX-2 protein. The induction of apoptosis by celecoxib involved the caspase pathways. Rofecoxib, up to its maximal concentration of 20 μm, did not inhibit cell growth or induce apoptosis.
Conclusions: Celecoxib may prove to be a very efficient component in the prevention and treatment of gastrointestinal tumors because it inhibits the growth of cancerous cells without affecting the growth of normal cells.