bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of Epigenetic Inactivation of
RASSF1A
with Poor Outcome in Human Neuroblastoma
Authors: Yang Qiwei , Zage Peter , Kagan David , Tian Yufeng , Seshadri Roopa , Salwen Helen R. , Liu Shuqing , Chlenski Alexandre , Cohn Susan L. 
Published: September 2005

Abstract
Purpose: To investigate the prevalence and potential clinical significance of epigenetic aberrations in neuroblastoma (NB).
Experimental Design: The methylation status of 11 genes that are frequently epigenetically inactivated in adult cancers was assayed in 13 NB cell lines. The prevalence of RASSF1A and TSP-1 methylation was also analyzed in 56 NBs and 5 ganglioneuromas by methylation-specific PCR. Associations between the methylation status of RASSF1A and TSP-1 and patient age, tumor stage, tumor MYCN status, and patient survival were evaluated.
Results: Epigenetic changes were detected in all 13 NB cell lines, although the pattern of gene methylation varied. The putative tumor suppressor gene RASSF1A was methylated in all 13 cell lines, and TSP-1 and CASP8 were methylated in 11 of 13 cell lines. Epigenetic changes of DAPK and FAS were detected in only small numbers of cell lines, whereas none of the cell lines had methylation of p16, p21, p73, RAR-β2, SPARC, or TIMP-3. RASSF1A was also methylated in 70% of the primary NB tumors tested, and TSP-1 methylation was detected in 55% of the tumors. RASSF1A methylation was significantly associated with age &gt;1 year (P &lt; 0.01), high-risk disease (P &lt; 0.016), and poor survival (P &lt; 0.001). In contrast, no association between TSP-1 methylation and prognostic factors or survival was observed.
Conclusions: Our results suggest that epigenetic inactivation of RASSF1A may contribute to the clinically aggressive phenotype of high-risk NB.
Differential Effects of Delivery of Omega-3 Fatty Acids to Human Cancer Cells by Low-Density Lipoproteins
versus
Albumin
Authors: Edwards Iris J. , Berquin Isabelle M. , Sun Haiguo , O’Flaherty Joseph T. , Daniel Larry W. , Thomas Michael J. , Rudel Lawrence L. , Wykle Robert L. , Chen Yong Q. 
Published: September 2005

Abstract
Purpose: Omega-3 (n-3) fatty acids (FA) have been proposed to confer tumor-inhibitory properties. In vivo, dietary FA are delivered to tumor cells by two main routes: low-density lipoproteins (LDL) and albumin complexes. High FA concentration in LDL and up-regulation of LDL receptors in tumor cells suggest that the LDL receptor pathway may be the major route for FA delivery. We compared effects of n-3FA delivered to human cancer cells by LDL and albumin.
Experimental Design: LDL was isolated from plasma of African Green monkeys fed diets enriched in fish oil (n-3 FA) or linoleic acid (n-6FA) and used to deliver FA to MCF-7 and PC3 cancer cells. Cell proliferation, apoptosis, and changes in global gene expression were monitored.
Results: Both LDL and albumin were effective in delivering FA to tumor cells and modifying the composition of cell phospholipids. The molar ratio of 20:4 (n-6) to 20:5 (n-3) in phosphatidylcholine and phosphatidylethanolamine was profoundly decreased. Although cell phospholipids were similarly modified by LDL and albumin-delivered FA, effects on cell proliferation and on transcription were markedly different. LDL-delivered n-3 FA were more effective at inhibiting cell proliferation and inducing apoptosis. Expression microarray profiling showed that a significantly higher number of genes were regulated by LDL-delivered than albumin-delivered n-3 FA with little overlap between the two sets of genes.
Conclusions: These results show the importance of the LDL receptor pathway in activating molecular mechanisms responsible for the tumor inhibitory properties of n-3FA.
2-Methoxyestradiol Inhibits Hypoxia-Inducible Factor 1α, Tumor Growth, and Angiogenesis and Augments Paclitaxel Efficacy in Head and Neck Squamous Cell Carcinoma
Authors: Ricker Justin L. , Chen Zhong , Yang Xin Ping , Pribluda Victor S. , Swartz Glenn M. , Van Waes Carter 
Published: September 2005

Abstract
Purpose: Head and neck squamous cell carcinomas have been reported to overexpress hypoxia-inducible factor (HIF)-1α, a transcription factor that promotes expression of angiogenesis factors and resistance to programmed and therapy-induced cell death. 2-Methoxyestradiol (2ME2) is a natural compound with HIF-1α inhibitory activity that is currently being evaluated in phase 1 and 2 clinical trials for advanced solid tumors and multiple myeloma. To our knowledge, this is the first study to evaluate the effects of 2ME2 in head and neck squamous cell carcinoma.
Experimental Design: In the present study, we investigated the effects of 2ME2 alone and in combination with paclitaxel, an active agent in recurrent or advanced head and neck squamous cell carcinoma.
Results: 2ME2 exhibited antiproliferative and cytotoxic effects in a panel of five head and neck squamous cell carcinoma cell lines in the 0.5 to 10 μmol/L range, including induction of G2-M blockade, caspase-3/7 activation, and apoptosis at 48 hours. 2ME2 resulted in decreased nuclear HIF-1α–binding activity and affected the expression of downstream genes, such as bid, a proapoptotic bcl-2 family member, and vascular endothelial growth factor, a proangiogenic cytokine. The up-regulation of Bid (57.5% at 12 hours, P &lt; 0.0006) and inhibition of vascular endothelial growth factor secretion (57.7% at 24 hours, P &lt; 0.015; and 50.3% at 48 hours, P &lt; 0.0006) could be partially attributed to the effects on HIF-1α, because HIF-1α small interfering RNAs produced similar effects. Finally, in vivo, in a xenograft model of head and neck squamous cell carcinoma using UM-SCC-11A cells, 2ME2 exhibited antitumor and antiangiogenic activity, as measured by CD31 immunostaining.
Conclusions: These results provide support for the use of 2ME2 in combination with paclitaxel for the treatment of recurrent or advanced head and neck squamous cell carcinoma.
Approval Summary
Authors: Dagher Ramzi , Li Ning , Abraham Sophia , Rahman Atiqur , Sridhara Raji , Pazdur Richard 
Published: September 2005

Abstract
Purpose: Docetaxel, a taxane previously approved for the treatment of breast cancer and non–small cell lung cancer, was approved by the United States Food and Drug Administration on May 19, 2004 for use in combination with prednisone for the treatment of metastatic androgen-independent (hormone-refractory) prostate cancer. The purpose of this summary is to review the database supporting this approval.
Experimental Design: In a randomized, global study enrolling 1,006 patients, two schedules of docetaxel were compared with mitoxantrone + prednisone as follows: MTZ q 3w, mitoxantrone 12 mg/m2 every 21 days + prednisone 5 mg twice a day for a total of 10 cycles; TXT q 3w, docetaxel 75 mg/m2 every 21 days + prednisone 5 mg twice a day for a total of 10 cycles; and TXT qw, docetaxel 30 mg/m2 days 1, 8, 15, 22, and 29 every 6 weeks + prednisone 5 mg twice a day for a total of 5 cycles.
Results: There was a statistically significant overall survival advantage shown for the TXT q 3w arm over MTZ q 3w (median survival 18.9 months versus 16.5 months, P = 0.0094). No overall survival advantage was shown for TXT qw compared with MTZ q 3w. The most commonly occurring adverse events included anemia, neutropenia, infection, nausea, sensory neuropathy, fluid retention, alopecia, nail changes, diarrhea, and fatigue.
Conclusions: This report describes the Food and Drug Administration review supporting this first approval of a combination therapy for hormone-refractory prostate cancer based on demonstration of a survival benefit.
ADAM8 as a Novel Serological and Histochemical Marker for Lung Cancer
Authors: Ishikawa Nobuhisa , Daigo Yataro , Yasui Wataru , Inai Kouki , Nishimura Hitoshi , Tsuchiya Eiju , Kohno Nobuoki , Nakamura Yusuke 
Published: September 2005

Abstract
Purpose and Experimental Design: We have been investigating genes involved in pulmonary carcinogenesis by examining gene expression profiles of non–small-cell lung cancers to identify molecules that might serve as diagnostic markers or targets for development of new molecular therapies. A gene encoding ADAM8, a disintegrin and metalloproteinase domain-8, was selected as a candidate for such molecule. Tumor tissue microarray was applied to examine expression of ADAM8 protein in archival lung cancer samples from 363 patients. Serum ADAM8 levels of 105 lung cancer patients and 72 controls were also measured by ELISA. A role of ADAM8 in cellular motility was examined by Matrigel assays.
Results: ADAM8 was abundantly expressed in the great majority of lung cancers examined. A high level of ADAM8 expression was significantly more common in advanced-stage IIIB/IV adenocarcinomas than in adenocarcinomas at stages I–IIIA. Serum levels of ADAM8 were significantly higher in lung cancer patients than in healthy controls. The proportion of the serum ADAM8-positive cases defined by our criteria was 63% and that for carcinoembryonic antigen was 57%, indicating equivalent diagnostic power of these two markers. A combined assay using both ADAM8 and carcinoembryonic antigen increased sensitivity because 80% of the lung cancer patients were then diagnosed as positive, whereas only 11% of 72 healthy volunteers were falsely diagnosed as positive. In addition, exogenous expression of ADAM8 increased the migratory activity of mammalian cells, an indication that ADAM8 may play a significant role in progression of lung cancer.
Conclusions: Our data suggest that ADAM8 should be useful as a diagnostic marker and probably as a therapeutic target.
Prognostic Impact of Hypoxia-Inducible Factors 1α and 2α in Colorectal Cancer Patients
Authors: Yoshimura Hiroshi , Dhar Dipok Kumar , Kohno Hitoshi , Kubota Hirofumi , Fujii Toshiyuki , Ueda Shuhei , Kinugasa Shoichi , Tachibana Mitsuo , Nagasue Naofumi 
Published: September 2005

Abstract
Purpose: Angiogenesis plays an important role in a multitude of biological processes including those of tumorigenesis and cancer progression. Hypoxia is the prime driving factor for tumor angiogenesis and the family of hypoxia-inducible factors (HIFs) plays a pivotal role in this process. The role of HIF in tumor angiogenesis has been underscored in different carcinomas but yet to be reported for colorectal carcinomas.
Experimental Design: In this study, we examined HIF [HIF-1α (HIF1) and HIF-2α (HIF2)] expression in 87 curatively resected colorectal carcinoma samples, and the results were correlated with clinicopathological factors, microvessel density, cyclooxygenase 2 expression, and patient prognosis.
Results: HIF1 (44.8%) was more frequently expressed than HIF2 (29.9%). Most of the clinicopathological factors representing the tumor aggressiveness were significantly correlated with overexpression of HIF2 but not with HIF1 expression. HIF2 expression had direct correlation with microvessel density and cyclooxygenase 2 expression. and, in contrast, HIF1 expression had a weak but significant inverse correlation in T1 and T2 tumors only. HIF2 expression alone and the combined expression of HIF1 and HIF2 had significant impact on patient survival. In the multivariate analysis, however, only the combined expression of HIF1 and HIF2 remained independently significant.
Conclusions: Taken together, our results suggest that HIF2 expression may play an important role in angiogenesis and that the combined expression of HIF1 and HIF2 may play an important role in tumor progression and prognosis of colorectal carcinomas. Therefore, HIF expression could be a useful target for therapeutic intervention.
Artificial Neural Networks Analysis of Surface-Enhanced Laser Desorption/Ionization Mass Spectra of Serum Protein Pattern Distinguishes Colorectal Cancer from Healthy Population
Authors: Chen Yi-ding , Zheng Shu , Yu Jie-kai , Hu Xun 
Published: September 2005

Abstract
Purpose: The low specificity and sensitivity of the carcinoembryonic antigen test makes it not an ideal biomarker for the detection of colorectal cancer. We developed and evaluated a proteomic approach for the simultaneous detection and analysis of multiple proteins for distinguishing individuals with colorectal cancer from healthy individuals.
Experimental Design: We subjected serum samples (including 55 colorectal cancer patients and 92 age- and sex-matched healthy individuals) from 147 individuals, for analysis by surface-enhanced laser desorption/ionization (SELDI) mass spectrometry. Peaks were detected with Ciphergen SELDI software version 3.0. Using a multilayer artificial neural network with a back propagation algorithm, we developed a classifier for separating the colorectal cancer groups from the healthy groups.
Results: The artificial neural network classifier separated the colorectal cancer from the healthy samples, with a sensitivity of 91% and specificity of 93%. Four top-scored peaks, at m/z of 5,911, 8,930, 8,817, and 4,476, were finally selected as the potential “fingerprints” for detection of colorectal cancer.
Conclusions: The combination of SELDI-TOF mass spectrometry with the artificial neural networks in the analysis of serum protein yields significantly higher sensitivity and specificity values for the detection and diagnosis of colorectal cancer.
Histone deacetylase inhibitors induce G2-checkpoint arrest and apoptosis in cisplatinum-resistant ovarian cancer cells associated with overexpression of the Bcl-2–related protein Bad
Authors: Strait Kevin A. , Warnick C. Terry , Ford Clyde D. , Dabbas Bashar , Hammond Elizabeth H. , Ilstrup Sarah J. 
Published: September 2005

Abstract
Trichostatin A produces predominantly G1 cell-cycle blockade and differentiation of the cisplatinum-sensitive A2780 ovarian cancer cell line. Given the propensity of ovarian tumors to become resistant to cisplatinum, often leading to cross-resistance to other agents, we have extended these observations by examining how the emergence of resistant phenotypes in A2780 cells affects the actions of histone deacetylase (HDAC) inhibitors. Trichostatin A exposure (100 ng/mL, 24 hours) induced ultrastructural differentiation of the “intrinsically” cisplatinum-resistant A2780-9M subline, with the reappearance of intercellular junctions and lumina containing primitive microvilli. Similar trichostatin A exposure in the acquired resistance A2780CP cells produced minimal differentiation consisting of occasional weak intercellular junctions. Independent of the differences in trichostatin A–induced differentiation, in both resistant sublines trichostatin A produced a similar reduction in cell viability, by &gt;90%, within 5 days of treatment. Diminished viability in both A2780-9M and CP cells was associated with the absence of cell cycle arrest in G1, resulting in predominant G2-checkpoint arrest accompanied by a 10- to 20-fold increase in Annexin V binding and the reemergence of apoptosis. Similar cell cycle arrests and apoptosis were also observed using other HDAC inhibitors and in other resistant ovarian cancer cell lines (OVCAR-3 and SK-OV-3). Trichostatin A–induced apoptosis in resistant cells is in sharp contrast to its effects on the parental cisplatinum-sensitive A2780 and normal MRC-5 fibroblast cell lines (predominant cycle arrest in G1 with no detectable apoptosis). Western immunoblot analysis indicated trichostatin A triggers apoptosis in resistant ovarian cancer cells via p53-independent activation of the intrinsic “mitochondrial” pathway, commensurate with induction of the Bcl-2–related protein Bad. These results suggest cisplatinum resistance alters the effects of HDAC inhibition through a shift in cell cycle arrest from the G1 to the G2 checkpoint and reactivation of the intrinsic mitochondrial apoptotic cascade.
Expression of multidrug transporterMRP4/ABCC4is a marker of poor prognosis in neuroblastoma and confers resistance to irinotecanin vitro
Authors: Norris Murray D. , Smith Janice , Tanabe Kara , Tobin Peter , Flemming Claudia , Scheffer George L. , Wielinga Peter , Cohn Susan L. , London Wendy B. , Marshall Glenn M. , Allen John D. , Haber Michelle 
Published: September 2005

AbstractMembers of the multidrug resistance–associated protein (MRP) family of transporters are believed to contribute to cytotoxic drug resistance and chemotherapy failure. We observed frequent MRP4 overexpression in aggressive primary neuroblastoma, a disease for which we have previously shown MRP1 to be a prognostic indicator. High MRP4 expression correlated with MYCN oncogene amplification and was significantly associated with poor clinical outcome. Although MRP4 is known to transport some nucleoside analogues, it has not previously been associated with resistance to drugs used to treat solid tumors. We now show that it mediates substantial resistance in vitro to the topoisomerase I poison irinotecan/CPT-11 and its active metabolite SN-38. These results suggest that MRP4 will be a useful prognostic marker for neuroblastoma and that clinical trials of irinotecan as a neuroblastoma treatment should monitor MRP4 expression. The same may be true for other tumor types expressing high levels of the transporter.
Dehydroxymethylepoxyquinomicin, a novel nuclear factor-κB inhibitor, induces apoptosis in multiple myeloma cells in an IκBα-independent manner
Authors: Tatetsu Hiro , Okuno Yutaka , Nakamura Miki , Matsuno Fumihiko , Sonoki Takashi , Taniguchi Izumi , Uneda Shima , Umezawa Kazuo , Mitsuya Hiroaki , Hata Hiroyuki 
Published: September 2005

Abstract
Nuclear factor-κB (NF-κB) is constitutively activated in multiple myeloma cells. Several proteasome inhibitors have been shown to be effective against multiple myeloma and may act by inhibiting degradation of IκBα. Here, we examined the biological effects of a new type of NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), which is reported to directly inhibit the cytoplasm-to-nucleus translocation of NF-κB. A multiple myeloma cell line, 12PE, which is defective for IκBα protein, was utilized to determine if IκBα is concerned with the action of DHMEQ. Meanwhile, U266 was used as a multiple myeloma cell line with normal IκBα. A proteasome inhibitor, gliotoxin, which is an inhibitor of degradation of phosphorylated IκBα, failed to inhibit translocation of NF-κB in 12PE. In contrast, DHMEQ equally inhibited translocation of NF-κB to the nucleus and induced apoptosis to both multiple myeloma cell lines, suggesting that apoptosis resulting from DHMEQ is IκBα independent. DHMEQ also induced apoptosis in freshly isolated multiple myeloma cells. After DHMEQ treatment, cleavage of caspase-3 and down-regulation of cyclin D1 were observed in both cell lines. In addition, administration of DHMEQ resulted in a significant reduction in tumor volume in a plasmacytoma mice model compared with control mice. Our results show that DHMEQ could potentially be a new type of molecular target agent for multiple myeloma.
Plasma vascular endothelial growth factor and interleukin-8 as biomarkers of antitumor efficacy of a prototypical erbB family tyrosine kinase inhibitor
Authors: Christensen James G. , Vincent Patrick W. , Klohs Wayne D. , Fry David W. , Leopold Wilbur R. , Elliott William L. 
Published: September 2005

AbstractCI-1033 (N-[4-[N-(3-chloro-4-fluorophenyl)amino-7-[3-(4-morpholynyl)propoxy]quinazolin-6-yl]acrylamide, PD 0183805-mesylate salt) was identified as a potent, selective inhibitor of erbB family tyrosine kinases, which are overexpressed in a number of solid tumors and have been shown to be involved in tumor progression. Because objective response of clinical patients to erbB-targeted therapies like CI-1033 has been observed only in a subset of cancer patients that exhibit the intended molecular targets, much emphasis has been placed on the identification of biomarkers of antitumor efficacy. Vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) were considered as potential biomarkers for CI-1033 due to ease of detection in patient plasma and showed roles in angiogenesis and cancer progression and positive regulation by the erbB receptor family. In the present studies, mice bearing established xenografts (A431 epidermoid carcinoma, H125 non–small cell lung carcinoma, SF767 glioblastoma, and MDA-MB-468 mammary carcinoma) were treated with efficacious and subefficacious doses of CI-1033, and plasma levels and xenograft gene expression of VEGF and IL-8 were evaluated. Oral administration of CI-1033 to tumor-bearing mice at efficacious doses resulted in markedly decreased levels of VEGF and/or IL-8 plasma levels and tumor mRNA levels relative to vehicle-treated control mice in xenograft models that exhibited evaluable levels of these markers. In contrast, subefficacious doses of CI-1033 did not significantly affect VEGF or IL-8 levels in any of the xenograft models. These studies indicate that plasma VEGF and IL-8 may have use as biomarkers of antitumor efficacy for epidermal growth factor receptor/erbB–targeted therapies such as CI-1033 and suggest that further clinical study of these markers in cancer patients are warranted.
A phase I clinical trial of a ribozyme-based angiogenesis inhibitor targeting vascular endothelial growth factor receptor-1 for patients with refractory solid tumors
Authors: Weng David E. , Masci Paul A. , Radka Susan F. , Jackson T. Elise , Weiss Patricia A. , Ganapathi Ram , Elson Paul J. , Capra William B. , Parker Vann P. , Lockridge Jennifer A. , Cowens J. Wayne , Usman Nassim , Borden Ernest C. 
Published: September 2005

AbstractPurpose: This study intended to determine the maximum tolerated dose, safety, pharmacokinetic variables, clinical response, and pharmacodynamic markers of daily s.c. administration of Angiozyme. Patients and Methods: Patients with refractory solid tumors were enrolled in a dose escalation and expanded cohort design. Dose escalation involved cohorts of patients at doses of 10, 30, 100, or 300 mg/m2/d for 29 days. A second component enrolled 15 additional patients at a daily dose of 100 mg/m2. Patients were eligible to continue on therapy until disease progression. Results: Thirty-one patients were enrolled and 28 were evaluable (range, 29–505 days; median, 89.5 days). A maximum tolerated dose was not defined by toxicity but rather by the maximal deliverable dose of 300 mg/m2/d. Grade 1 to 2 injection site reactions were the most common toxicities. One patient in the 300 mg/m2 group experienced a reversible grade 3 injection site reaction. Angiozyme showed dose-dependent plasma concentrations with good bioavailability. Surrogate markers showed Angiozyme localization in tumor biopsies and a significant increase in serum von Willebrand factor antigen, a marker for endothelial cell dysfunction. Although Angiozyme-reactive antibody production was noted for some patients, no antibody-related adverse events were noted. Seven of 28 (25%) evaluable patients had stable disease for ≥6 months, with the longest treatment duration of ≥16 months. Two patients (nasopharyngeal carcinoma and melanoma) showed minor responses. Conclusion: Angiozyme was well tolerated with satisfactory pharmacokinetic variables for daily s.c. dosing. Results have provided the basis for subsequent clinical trials of this first-of-class biologically targeted therapeutic.