bluuebunny/crossref_metadata_2025_split huggingface dataset:
AMN107, a Novel Aminopyrimidine Inhibitor of Bcr-Abl, Has In vitro Activity against Imatinib-Resistant Chronic Myeloid Leukemia
Authors: Golemovic Mirna , Verstovsek Srdan , Giles Francis , Cortes Jorge , Manshouri Taghi , Manley Paul W. , Mestan Jürgen , Dugan Margaret , Alland Leila , Griffin James D. , Arlinghaus Ralph B. , Sun Tong , Kantarjian Hagop , Beran Miloslav 
Published: September 2005

Abstract
Resistance to or intolerance of imatinib in patients with Philadelphia chromosome–positive chronic myelogenous leukemia (CML) has encouraged the development of more potent Bcr-Abl inhibitors. AMN107 is a novel, orally bioavailable ATP-competitive inhibitor of Bcr-Abl. The effects of AMN107 were compared with those of imatinib on imatinib-sensitive (KBM5 and KBM7) and imatinib-resistant CML cell lines (KBM5-STI571R1.0 and KBM7-STI571R1.0). Compared with the antiproliferative activity of imatinib, AMN107 was 43 times more potent in KBM5 (IC50 of 11.3 versus 480.5 nmol/L) and 60 times more potent in KBM7 (IC50 of 4.3 versus 259.0 nmol/L) cells. IC50 for AMN107 and imatinib were 2,418.3 and 6,361.4 nmol/L, respectively, in KBM5-STI571R1.0, and 97.2 and 2,497.3 nmol/L, respectively, in KBM7-STI571R1.0 cells. AMN107 inhibited autophosphorylation of Bcr-Abl kinase more effectively than imatinib in all cell lines. They had similar effects on cell cycle progression and apoptotic response in these cell lines. Among severe combined immunodeficient mice bearing KBM5 cells, mean survival times of groups treated with 10, 20, and 30 mg/kg/d of AMN107, starting day 20 after leukemic cell grafting and continuing for 20 days, were 144%, 159%, and 182%, respectively, compared with controls. These results strongly support investigation of the clinical efficacy of AMN107 in patients with CML.
The Cyclin-Dependent Kinase Inhibitor UCN-01 Plus Cisplatin in Advanced Solid Tumors: A California Cancer Consortium Phase I Pharmacokinetic and Molecular Correlative Trial
Authors: Lara Primo N. , Mack Philip C. , Synold Timothy , Frankel Paul , Longmate Jeff , Gumerlock Paul H. , Doroshow James H. , Gandara David R. 
Published: September 2005

Abstract
Background: UCN-01 (7-hydroxy-staurosporine) is a novel antineoplastic agent targeting cyclin-dependent kinases, which shows potent in vitro and in vivo activity against a broad range of tumor types. Our group has previously shown that UCN-01 potentiates the apoptotic response of agents such as cisplatin in vitro by preventing sequence-specific abrogation of G2 arrest caused by DNA-damaging chemotherapies.
Patients and Methods: This National Cancer Institute–sponsored phase I trial was designed to determine the safety, maximum tolerated dose, and pharmacokinetics of escalating doses of cisplatin in combination with UCN-01 in patients with advanced malignant solid tumors, as well as to do molecular correlative studies on tumor specimens. Cisplatin was infused over 1 hour before UCN-01 (45 mg/m2/d) given as a 72-hour continuous infusion. Escalation of cisplatin was planned through five dose levels at 20, 30, 45, 60, and 75 mg/m2.
Results: Ten patients were accrued. Accrual was halted at dose level 2 (cisplatin, 30 mg/m2) due to dose-limiting toxicities consisting of grade 5 sepsis with respiratory failure associated with grade 3 creatinine (one patient) and grade 3 atrial fibrillation (one patient). Plasma and salivary pharmacokinetics of UCN-01 were unaffected by cisplatin. Pretreatment and posttreatment tumor biopsies showed that UCN-01 was active against a key molecular target, the checkpoint kinase Chk1.
Conclusions: This phase I trial failed to achieve targeted therapeutic dose levels of cisplatin when combined with prolonged infusion UCN-01. However, because preclinical data indicate that UCN-01 potentiates response to platinum, further studies with alternative dose schedules of the combination, or with other platinum analogues, are warranted.
Combination Therapy with Interleukin-6 Receptor Superantagonist Sant7 and Dexamethasone Induces Antitumor Effects in a Novel SCID-huIn vivoModel of Human Multiple Myeloma
Authors: Tassone Pierfrancesco , Neri Paola , Burger Renate , Savino Rocco , Shammas Masood , Catley Laurence , Podar Klaus , Chauhan Dharminder , Masciari Serena , Gozzini Antonella , Tagliaferri Pierosandro , Venuta Salvatore , Munshi Nikhil C. , Anderson Kenneth C. 
Published: September 2005

AbstractInterleukin-6 (IL-6) protects multiple myeloma cells against apoptosis induced by glucocorticoids. Here, we investigated whether inhibition of the IL-6 signaling pathway by the IL-6 receptor superantagonist Sant7 enhances the in vivo antitumor effects of dexamethasone on the IL-6–dependent multiple myeloma cell line INA-6. For this purpose, we used a novel murine model of human multiple myeloma in which IL-6–dependent INA-6 multiple myeloma cells were directly injected into human bone marrow implants in severe combined immunodeficient (SCID) mice (SCID-hu). The effect of in vivo drug treatments on multiple myeloma cell growth was monitored by serial determinations of serum levels of soluble IL-6 receptor (shuIL-6R), which is released by INA-6 cells and served as a marker of tumor growth. In SCID-hu mice engrafted with INA-6 cells, treatment with either Sant7 or dexamethasone alone did not induce significant reduction in serum shuIL-6R levels. In contrast, the combination of Sant7 with dexamethasone resulted in a synergistic reduction in serum shuIL-6R levels after 6 consecutive days of treatment. Gene expression profiling of INA-6 cells showed down-regulation of proliferation/maintenance and cell cycle control genes, as well as up-regulation of apoptotic genes in multiple myeloma cells triggered by Sant7 and dexamethasone combination. In vitro colony assays showed inhibition of myeloid and erythroid colonies from normal human CD34+ progenitors in response to dexamethasone, whereas Sant7 neither inhibited colony growth nor potentiated the inhibitory effect of dexamethasone. Taken together, these results indicate that inhibition of IL-6 signaling by Sant7 significantly potentiates the therapeutic action of dexamethasone against multiple myeloma cells, providing the preclinical rationale for clinical trials of Sant7 in combination with dexamethasone to improve patient outcome in multiple myeloma.
Prognostic Implications of Cell Cycle, Apoptosis, and Angiogenesis Biomarkers in Non–Small Cell Lung Cancer: A Review
Authors: Singhal Sunil , Vachani Anil , Antin-Ozerkis Danielle , Kaiser Larry R. , Albelda Steven M. 
Published: September 2005

AbstractLung cancer is the leading cause of cancer death in the U.S. with survival restricted to a subset of those patients able to undergo surgical resection. However, even with surgery, recurrence rates range from 30% to 60%, depending on the pathologic stage. With the advent of partially effective, but potentially toxic adjuvant chemotherapy, it has become increasingly important to discover biomarkers that will identify those patients who have the highest likelihood of recurrence and who thus might benefit most from adjuvant chemotherapy. Hundreds of papers have appeared over the past several decades proposing a variety of molecular markers or proteins that may have prognostic significance in non–small cell lung cancer. This review analyzes the largest and most rigorous of these studies with the aim of compiling the most important prognostic markers in early stage non–small cell lung cancer. In this review, we focused on biomarkers primarily involved in one of three major pathways: cell cycle regulation, apoptosis, and angiogenesis. Although no single marker has yet been shown to be perfect in predicting patient outcome, a profile based on the best of these markers may prove useful in directing patient therapy. The markers with the strongest evidence as independent predictors of patient outcome include cyclin E, cyclin B1, p21, p27, p16, survivin, collagen XVIII, and vascular endothelial cell growth factor.
Epidermal Growth Factor–Induced Cyclooxygenase-2 Expression Is Mediated through Phosphatidylinositol-3 Kinase, Not Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase, in Recurrent Respiratory Papillomas
Authors: Wu Rong , Abramson Allan L. , Shikowitz Mark J. , Dannenberg Andrew J. , Steinberg Bettie M. 
Published: September 2005

Abstract
Purpose: Recurrent respiratory papillomas, caused by human papillomaviruses, are premalignant tumors that overexpress the epidermal growth factor receptor (EGFR). The goals of this study were as follows: (a) to evaluate the expression of cyclooxygenase-2 (COX-2) in papillomas, (b) to investigate the role of EGFR signaling in COX-2 expression, and (c) to determine whether COX-2 activity is important for the growth of papilloma cells.
Experimental Design: Immunohistochemistry, Western blotting, and real-time PCR were used to determine levels of COX-2 in papilloma and normal laryngeal tissue. Explant cultures of both normal laryngeal and papilloma cells were used to define the signaling pathways that regulate COX-2 expression and investigate the potential of targeting COX-2 as a strategy to suppress papilloma growth.
Results: COX-2 levels were markedly increased in papillomas. In vitro studies suggested that overexpression in papillomas reflected activation of EGFR→phosphatidylinositol 3-kinase signaling. Treatment with prostaglandin E2 (PGE2) induced COX-2, whereas celecoxib, a selective COX-2 inhibitor, suppressed levels of COX-2, suggesting a positive feedback loop. Moreover, treatment with PGE2 stimulated papilloma cell growth, whereas celecoxib suppressed proliferation and induced apoptosis.
Conclusions: Overexpression of COX-2 in papillomas seems to be a consequence of enhanced EGFR→phosphatidylinositol 3-kinase signaling. We propose a positive feedback loop for COX-2 expression, with induction of COX-2 resulting in enhanced PGE2 synthesis and further expression of COX-2 that contributes to the growth of papillomas in vivo. These data strengthen the rationale for evaluating whether nonsteroidal anti-inflammatory drugs, prototypic COX inhibitors, will be useful in the management of respiratory papillomas.
The Potential Role of Proteasome Inhibitors in the Treatment of Lung Cancer
Authors: Bunn Paul A. 
Published: September 2005

Abstract
Bortezomib (PS-341, Velcade, Millennium Pharmaceuticals, Cambridge, MA) is a novel inhibitor of the proteasome. The proteasome plays a critical role in the degradation and, therefore, regulation of many proteins involved in cell cycle regulation, apoptosis, and angiogenesis. Bortezomib inhibits the growth of lung cancer cell lines in vitro and in vivo in athymic nude mouse xenografts. Bortezomib produces a G2-M arrest, increases in cyclin A and cyclin B, increases in p21, and increases apoptosis in these preclinical models. Phase I studies established that a dose of 1.4 mg/m2 given i.v. on days 1, 4, 8, and 11 of a 3-week cycle produced acceptable toxicity and serum levels that resulted in proteasome inhibition. Phase II studies showed high-response rates in refractory multiple myeloma. These response rates were sufficiently high to allow accelerated approval of bortezomib by the Food and Drug Administration for this indication. Phase II trials in both non-small cell lung cancer and small cell lung cancer are in progress. A number of Phase I combination studies are also underway. Hopefully, bortezomib will show sufficient activity in lung cancer to improve survival in this dread disease.
Cetuximab in Advanced Non-Small Cell Lung Cancer
Authors: Govindan Ramaswamy 
Published: September 2005

Abstract
The epidermal growth factor receptor (EGFR) is frequently overexpressed in non-small cell lung cancer (NSCLC). EGFR activation results in phosphorylation of several downstream intracellular substrates involved in cell proliferation, angiogenesis, and inhibition of apoptosis. Cetuximab (C225, Erbitux), a monoclonal antibody directed against ligand binding in the extracellular domain of EGFR, inhibits tumor growth and is synergistic with chemotherapy and radiation. Cetuximab has been studied in combination with chemotherapy in previously untreated metastatic NSCLC. The response rates in preliminary reports range from 29% to 53%. In patients with refractory/recurrent NSCLC, the combination of docetaxel and cetuximab resulted in a promising response rate of 28%, higher than the typical response rates seen with docetaxel monotherapy in this setting. Addition of cetuximab to chemotherapy is generally well tolerated. Molecular mechanisms predicting response to cetuximab therapy are currently not well understood. Studies are ongoing to assess the single-agent activity of cetuximab in metastatic NSCLC.
Anti-Vascular Endothelial Growth Factor Monoclonals in Non-Small Cell Lung Cancer
Authors: Sandler Alan B. , Johnson David H. , Herbst Roy S. 
Published: September 2005

Abstract
There is an urgent need for new therapies to treat non-small cell lung cancer (NSCLC) because current chemotherapy regimens are of limited effectiveness. The role of vascular endothelial growth factor in promoting tumor angiogenesis, in maintaining existing vasculature, and in resistance to traditional therapies, together with its negative prognostic significance in NSCLC, make it an appropriate target for therapy. Bevacizumab (Avastin), a monoclonal antibody directed against vascular endothelial growth factor, has shown promise in treating a number of different cancers. In a recent Phase II trial in patients with advanced metastatic NSCLC, the addition of bevacizumab to standard carboplatin/paclitaxel chemotherapy significantly increased the time to progression and increased the response rate when compared with chemotherapy alone. This was particularly impressive in the subset of patients with non-squamous histology. Bevacizumab is generally well tolerated and did not appear to increase the incidence or severity of nausea/vomiting, neuropathy and renal toxicity, which are typically associated with carboplatin/paclitaxel chemotherapy. Adverse events in Phase I and II studies included hypertension, thrombosis, proteinuria (with occasional nephrotic syndrome), and epistaxis. Serious tumor-related bleeding episodes (hemoptysis/hematemesis) seem to be the main safety concern in patients with NSCLC, with squamous cell histology as a possible risk factor. Present ongoing studies are under way in NSCLC including (a) a Phase II neo-adjuvant study in combination with paclitaxel and carboplatin in patients with stage IB–IIA NSCLC; (b) a Phase I/II study of bevacizumab in combination with the epidermal growth factor receptor tyrosine kinase inhibitor agent, Tarceva, in patients with previously treated NSCLC; and (c) an Eastern Cooperative Group randomized Phase III study of paclitaxel and carboplatin with/without bevacizumab in patients with previously untreated IIIB (malignant pleural effusion) or metastatic NSCLC. These studies will help to establish the role of bevacizumab in NSCLC.
Kinase Inhibition with BAY 43–9006 in Renal Cell Carcinoma
Authors: Ahmad Tanya , Eisen Tim 
Published: September 2005

AbstractBAY 43–9006 is an oral inhibitor of CRAF, wild-type BRAF, mutant V599E BRAF, vascular endothelial growth factor receptor (VEGFR) 2, VEGFR3, mVEGFR2, FLT-3, platelet-derived growth factor receptor, p38, and c-kit among other kinases. A Phase I study of BAY 43–9006 identified 400 mg orally twice daily as the recommended Phase II dose. The Phase II results of a study of BAY 43–9006 at 400 mg orally twice daily were particularly interesting in patients with renal cell carcinoma. Data from the first 41 patients with renal cell carcinoma showed that 30% of patients had stable disease (defined as between 25% reduction and 25% growth), 40% had responded (defined as &gt;25% reduction), and 30% had progressed. Disease could be stabilized for periods in excess of a year. Some lesions became cystic and could actually enlarge while developing a low attenuation core. This phenomenon is recognized in the treatment of gastrointestinal stromal tumors with imatinib mesylate. The toxic effects of BAY 43–9006 were manageable and included hypertension, edema, diarrhea, hand and foot syndrome, rash, and hair loss where the rash involved the scalp. There was an impression of tachyphylaxis such that patients who required a dose reduction could be restored to full dose after a few months. A Phase III randomized, placebo-controlled trial of BAY 43–9006 has started for patients whose renal cell carcinoma has progressed within 6 months of immunotherapy. Combination studies with interferon, interleukin 2, bevacizumab, and chemotherapy are under consideration. The therapeutic targets of BAY 43–9006 in renal cell carcinoma remain unclear. Unlike melanoma, BRAF mutations have not been found in renal cell carcinoma. Other candidate targets include VEGFR2 and VEGFR3.
Functional Characterization of the Bladder Cancer Marker, BLCA-4
Authors: Van Le Thu-Suong , Myers Julie , Konety Badrinath R. , Barder Timothy , Getzenberg Robert H. 
Published: September 2005

Abstract
Introduction: Bladder cancer is a common disease of the genitourinary tract for which the development of a noninvasive detection technique would have a significant impact on disease management. One of our previously identified bladder cancer-specific proteins, BLCA-4, appears to be associated with a “field effect” of the disease, and in clinical trials is able to separate individuals with bladder cancer from those without the disease with high sensitivity and specificity. The potential clinical utility of this marker has led to the analysis of its function in bladder cancer pathobiology.
Experimental Design: To additionally analyze the specificity of this marker, the expression in the urine of a variety of benign urologic conditions was analyzed. After cloning the gene encoding BLCA-4, functional aspects of the protein were analyzed by overexpressing it in cell systems, as well as its interaction with other transcription factors and in gel mobility shift assays. Finally, to determine the timing of expression in relation to the observance of bladder cancer, an animal model of the disease was examined.
Results: Expression of BLCA-4, the cDNA of which reveals that it is a novel member of the ETS transcription factor family, is not found in benign urologic conditions. Overexpression leads to increased growth rates of cells, and the protein interacts with other transcription factors. In vivo studies reveal that BLCA-4 expression occurs significantly before the observance of grossly visible tumors in an animal model of the disease.
Conclusions: BLCA-4 is a bladder cancer marker that is highly specific and occurs early in the development of the disease. It appears to be a transcription factor that may play a role in the regulation of the gene expression in bladder cancer. BLCA-4 is a marker with significant clinical utility that may have an active role in the disease.
Response of Non–Small Cell Lung Cancer Cells to the Inhibitors of Phosphatidylinositol 3-Kinase/Akt- and MAPK Kinase 4/c-Jun NH2-Terminal Kinase Pathways: An Effective Therapeutic Strategy for Lung Cancer
Authors: Lee Ho-Young , Oh Seung-Hyun , Suh Young-Ah , Baek Jin Hyen , Papadimitrakopoulou Vali , Huang Suyun , Hong Waun Ki 
Published: September 2005

Abstract
Purpose: We previously showed that phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) pathways cooperate to promote non–small cell lung cancer (NSCLC) cell proliferation in vitro. This study was designed to explore whether inhibition of these pathways effectively inhibits NSCLC tumor growth in vivo.
Experimental Design: The effects of PI3K/Akt inhibitors {LY294002, adenoviruses expressing dominant-negative mutant of the p85α adaptor subunit of PI3K (Ad-dnp85α), dominant-negative Akt [Ad-HA-Akt(KM)], or PTEN (Ad-PTEN)}, MKK4/c-jun NH2-terminal kinase (JNK) inhibitor [SP600215, adenovirus expressing dominant-negative MKK4, Ad-MKK4(KR)], and their combinations on proliferation and apoptosis in NSCLC cells were tested in vitro and in vivo using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, a flow cytometry-based terminal deoxynucleotidyl transferase–mediated nick-end labeling assay, Western blot and immunohistochemical analyses, and an NSCLC xenograft tumor model.
Results: Ad-dnp85α significantly inhibited proliferation of a subset of NSCLC cell lines used in our study. Intratumoral injection of Ad-dnp85α induced a significant decrease in the growth of H1299 NSCLC xenograft tumors. Concurrent inhibition of the PI3K/Akt and MKK4/JNK pathways showed enhanced antiproliferative effects on H1299 cells in vitro and in vivo by increasing apoptosis.
Conclusions: PI3K/Akt and MKK4/JNK pathways cooperate to stimulate NSCLC cell proliferation by maintaining cell survival, suggesting that simultaneously targeting these two pathways might be an effective therapeutic strategy against NSCLC.
Estrogen-Responsive Finger Protein as a New Potential Biomarker for Breast Cancer
Authors: Suzuki Takashi , Urano Tomohiko , Tsukui Tohru , Horie-Inoue Kuniko , Moriya Takuya , Ishida Takanori , Muramatsu Masami , Ouchi Yasuyoshi , Sasano Hironobu , Inoue Satoshi 
Published: September 2005

Abstract
Purpose: Estrogen-responsive finger protein (Efp) is a member of RING finger-B box-Coiled Coil family and is also a downstream target of estrogen receptor α. Previously, Efp was shown to mediate estrogen-induced cell growth, which suggests possible involvement in the development of human breast carcinomas. In this study, we examined expression of Efp in breast carcinoma tissues and correlated these findings with various clinicopathologic variables.
Experimental Design: Thirty frozen specimens of breast carcinomas were used for immunohistochemistry and laser capture microdissection/real-time PCR of Efp. Immunohistochemistry for Efp was also done in 151 breast carcinoma specimens fixed with formalin and embedded in paraffin wax.
Results: Efp immunoreactivity was detected in breast carcinoma cells and was significantly associated with the mRNA level (n = 30). Efp immunoreactivity was positively associated with lymph node status or estrogen receptor α status and negatively correlated with histologic grade or 14-3-3σ immunoreactivity (n = 151). Moreover, Efp immunoreactivity was significantly correlated with poor prognosis of breast cancer patients, and multivariate analyses of disease-free survival and overall survival for 151 breast cancer patients showed that Efp immunoreactivity was the independent marker.
Conclusions: Our data suggest that Efp immunoreactivity is a significant prognostic factor in breast cancer patients. These findings may account for an oncogenic role of Efp in the tumor progression of breast carcinoma.