bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1530: Modulation of drug transporter expression in pancreatic cancer cells by indole-3-carbinol and gemcitabine: Potential transporter-targeted therapy
Authors: Lyn-Cook Beverly D. , Davis Cornelius , Wiley Kenneth , Word Beverly , Hammons George 
Published: February 2011

Abstract
Increased expression of drug transporters that induces multidrug resistance is a critical event in poor prognosis and treatment for numerous cancers, particularly pancreatic cancer. Due to its aggressive and resistance characteristics, prognosis is often fatal. Recently, investigators have focused on the use of inhibitors of proteins transcribed by various drug transporters as a potential target for improved therapy of various chemotherapeutics. Gemcitabine is the current treatment for pancreatic cancer, although some patients respond poorly to the treatment. Interindividual differences in expression of drug transporters relating to drug resistance has been a major factor in different drug outcomes. In the present study, pancreatic cancer cells (Panc-1 and SU86. 86) showed expression of the following drug transporters, ABCB1, ABCA5, MRP5, SLCO1B1, and SLC5A6. Gemcitabine treatment alone down-regulated expression of ABCA5, SLCO1B1, and SLC5A6 (P&lt;0.05) transporters. Gemcitabine (0.1 µM) or I3C (100 µM) alone had no effect on ABCB1 expression. However, combination of gemcitabine (0.1µM) and indole-3-carbinol(100 µM) significantly down-regulated ABCB1. ABCB1 codes for the multidrug protein, pgp. This combination significantly inhibited growth of pancreatic cancer cells by 70%. Gemcitabine and indole-3 carbinol also decreased expression of MRP5 expression. These data suggest that dietary agents in combination with chemotherapeutics are potential inhibitors of multidrug resistance by down-regulating these proteins thus allowing for increased efficacy of the drug for treatment of the cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1530.
Abstract 154: Genome-wide profiling of histone and DNA methylation in prostate cells during EMT and malignant transformation
Authors: Ke Xi-Song , Qu Yi , Li Wen-Cheng , Yang Cheng , Rotter Varda , Oyan Anne Margrete , Kalland Karl-Henning 
Published: February 2011

Abstract
The loss of epithelial characteristics and the acquisition of a migratory phenotype, referred to as epithelial to mesenchymal transition (EMT), is a crucial event in tumor metastasis. Epigenetic modifications have been shown to be very critical in gene regulation during carcinogenesis, yet the role in EMT remains to be clarified. We report here a genome-wide analysis of histone methylation (H3K4me3 and H3K27me3), DNA methylation (DNAMe) and gene expression profiles in epithelial cells (EP156T) and their progeny mesenchymal cells (EPT1) and transformed cells (EPT2) in a cell culture model of stepwise prostate carcinogenesis. We found that H3K4me3 and H3K27me3 are very clear marks of active or repressed genes, while DNA methylation is only slightly associated with gene repression in all three cell lines. However, DNA methylation is a strong silencing mark when H3K4me3/DNAMe bivalently marked genes were excluded. Analysis of the transcription activities of genes with bivalent marks showed that H3K4me3/K27me3 is a repressive mark while H3K4me3/DNAMe is an active mark of gene expression. In individual genes, the transcription activities of genes with bivalent marks most likely correspond to the stronger mark. Furthermore, quantitative changes of H3K4me3 or H3K27me3 during EMT were correlated positively and negatively to activated and repressed transcription, respectively. Finally, a set of critical genes during EMT, including epithelial cell junction genes and the EMT inducers, FGFRs, were identified to show consistent changes concerning epigenetic modification and gene expression. All these findings provide the first blueprint of genome-wide epigenetic modification during EMT in prostate cells.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 154.
Abstract 1543: Up-regulation of CD52 enhances the resistance against bortezomib in multiple myeloma cells
Authors: Oh Jeong In , Park Juwon , Lee Chansu , Kim Byung-Su , Kwon Jung Hye , Kim Byoung Kook , Ahn Kwang-Sung , Yoon Sung-Soo 
Published: February 2011

Abstract
Bortezomib has excellent clinical activity in patients with multiple myeloma (MM). Clinical efficacy has been hampered by the emergence of drug-resistance phenomena. Verification of molecular mechanism by which resistance emerges is crucial for improved treatment outcome in MM. In this study, we established bortezomib resistance MM cells (U266/velR) and examined the biologic characteristics. In microarray analysis, 294 genes expressions were changed more than two-fold or greater and seven putative genes were selected by further analyzing microarray dataset. Those gene expressions between U266/velR and its control were confirmed using real-time RT-PCR. Among them, CD52, the lymphocyte surface marker, could be a target molecule to overcome bortezomib resistance. CD52 gene expression was examined in 6 different MM cell lines. Its expression was detected in U266, ARH77, and HS-sultan, but not in RPMI8226, IM9 and 536MM. The expression level of CD52 was correlated to the response of Bortezomib sensitivity. FASC analysis showed that CD52+ populations in U266/velR were 2.7 fold higher than those in control. When U266 cells were serially treated with Bortezomib, CD52 expression was gradually increased. In transfection analysis using full length cDNA of CD52 gene, transfected RPMI8226 cells were more resistant than parental cell. Our results suggested that Alemtuzumab was proposed as a therapeutic agent in bortezomib resistant myeloma patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1543.
Abstract 155: A comparison of DNA methylation in identical twins discordant for Hodgkin lymphoma
Authors: Cozen Wendy , Wang Jun , Siegmund Kim , Triche Timothy , Weisenberger Daniel , Van Den Berg David , Hamilton Ann , Hwang Amie , Mack Thomas M. 
Published: February 2011

Abstract
DNA methylation is an epigenetic change that may affect gene expression. Environmental determinants are largely unknown but strongly suspected. Because twins are matched on genome and to some extent, early life exposures, a comparison of DNA methylation between twins is of more interest than one between unrelated individuals.
To evaluate the possibility of an association between DNA methylation and young adult Hodgkin lymphoma (HL), DNA samples from blood or saliva were collected from both members of 25 identical twin pairs in whom one twin had developed HL prior to age 50 (discordant pairs). The median time since diagnosis was 16 years. DNA methylation status at 27,578 loci in 14,475 genes was measured in each sample using the Illumina Infinium methylation assay. We measured any difference (&lt; or &gt; 0) in the level of DNA methylation at each locus between the case and the unaffected co-twin and applied a paired t-test.
The overall pattern indicated that cases had higher levels of DNA methylation at loci with lower average DNA methylation levels, but the reverse was true at loci with higher overall levels of DNA methylation (e.g., here the cases had lower levels). With respect to specific loci, the HL case consistently had a higher level of DNA methylation compared to his/her unaffected co-twin at locus cg24693053 in the MFSD7 (major facilitator superfamily domain containing 7) gene in 22/25 pairs; this was also the locus with the most significant p-value (p= 0.0000332). Twenty-two out of 25 cases had a lower level of DNA methylation than their unaffected co-twin at loci cg17385448 in the AGMAT (Agmatine ureohydrolase [agmatinase]) gene (p= 0.0001587) and cg09809672 in the EDARADD (EDAR-associated death domain) gene (p= 0.003775846).
Seventeen out of 19 cases with the nodular sclerosis subtype had consistently higher DNA methylation levels at 9 loci and lower levels at 7 loci compared to their unaffected co-twin (binomial test p=0.0007). There was no overall effect on the pattern of methylation by time since diagnosis.
We observed suggestive differences in DNA methylation levels in normal peripheral blood mononuclear cells collected from young adult HL patients in remission relative to their unaffected identical co-twins. The differences may have resulted from HL disease or treatment, or could have pre-dated the diagnosis. The results are compatible with a role of the cumulative environment on DNA methylation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 155.
Abstract 1550: Small molecule inhibitors of ezrin as anti-metastatic agents in osteosarcoma
Authors: Bulut Gulay , Chen Kevin , Glasgow Eric , Hong Sung-Hyeok , Lee Hyun-Shik , Kosturko George , Toretsky Jeffrey A. , Daar Ira , Khanna Chand , Uren Aykut 
Published: February 2011

Abstract
Osteosarcoma (OS) is the most common type of primary bone cancer and the third most common cancer in children and adolescents. Current combination modalities have improved OS treatment, but did not have a major improvement on patient survival. Thus targeting underlying molecular events can provide dramatic benefits especially for the treatment of patients with fatal metastatic disease. Recently it is shown in a mouse model of OS that high ezrin expression is linked to pulmonary metastasis, providing an early survival advantage for cancer cells reaching the lung. Ezrin, a member of the ERM (Ezrin/Radixin/Moesin) family is conserved through evolution both structurally and functionally. By regulating membrane-cytoskeleton complexes, it plays key roles in normal cellular processes like maintenance of membrane dynamics, survival, adhesion, motility, cytokinesis, phagocytosis and integration of membrane transport with signaling pathways. Due to its critical role in these cellular functions and relevance to metastasis, ezrin is a validated molecular target for prevention of metastasis in OS. In order to identify small molecules that directly interact with recombinant ezrin protein, we screened a small molecule library by surface plasmon resonance technology (Biacore). Initial hits from this primary screen were then evaluated in functional assays. We tested our small molecules for inhibiting ezrin mediated chemotaxis in cell culture, mimicking ezrin morpholino phenotype in zebrafish development, inhibiting ezrin phosphorylation and ezrin-actin interaction, effecting xenopus embryo development and inhibiting lung metastasis of osteosarcoma cells in a mouse lung organ culture assay. Results from these secondary functional assays, binding kinetics values from Biacore experiments and drugability of the chemical structures allowed us to pick two lead compounds. In summary, we discovered two lead compounds that directly bind to ezrin protein with ∼10uM affinity and inhibit its function in multiple independent assays. These molecules form the foundation of new potential therapeutic agents for osteosarcoma metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1550.
Abstract 1552: Isothiocyanates suppress human lung cancer cells metastasis
Authors: Yan Huiqin , Zhu Yu , Wu Xiang , Liu Boning , Li Ying , Liu Yunde , Zhou Qinghua , Xu Ke 
Published: February 2011

Abstract
Lung cancer is one of the most aggressive cancer types, and is the leading cause of cancer-related deaths worldwide. Metastasis is of great importance to the clinical management of cancer since it causes 90% of deaths from solid tumours. Therefore the development of novel anti-metastasis drugs becomes one of the most active fields in cancer research. Isothiocyanates are natural compounds found in consumable cruciferous vegetables. They have been shown to have the ability to inhibit chemical carcinogenesis by a wide variety of chemical carcinogens in animal models, inhibiting tumorigenesis in the lung, stomach, colon, liver, etc. Recent studies have also shown that isothiocyanates have antitumor activity, inhibiting several types of cultured human cancer cells growth, such as leukemia, prostate cancer and breast cancer. Our previous study also showed that isothiocyanates inhibit human lung cancer A549 cell growth. In the present study, we investigated the inhibitory effects of isothiocyanates on human lung cancer cell metastasis. We established a high-metastatic human large cell lung cancer cell line L9981, and found that both benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC) inhibited L9981 cells growth in a dose-dependent manner, the IC50 values were 5.0±0.22 μM and 9.7±0.39 μM, respectively. Apoptosis was induced at 20 μM after 24 h. Transwell migration assay showed that the metastatic abilities of L9981 cells were suppressed by 96%, and metastasis-correlated genes were modulated. Cell cycle was arrested at G2/M phase. BITC and PEITC treatment resulted in reactive oxygen species (ROS) accumulation and severe glutathione (GSH) depletion. Akt activation was diminished. At transcription level, both nuclear transcription factors NFκB and AP-1 activities were suppressed. NFκB activities were reduced to 28.8% and 68.5% by BITC and PEITC, respectively; AP-1 activities were reduced to 17.8% and 80.9% by BITC and PEITC, respectively. Our results showed that BITC and PEITC suppress human lung cancer cells metastasis by induction of apoptosis, modulation of metastasis correlated gene expression, and induction of oxidative stress. This study indicates the potential use of isothiocyanates in treatment of advanced lung cancer. The signal transduction pathways and validation of cellular therapeutic targets of these isothiocyanates are under investigation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1552.
Abstract 1553: Activity of new matrix metalloproteinase inhibitors designed from 3D structure
Authors: Garcia-Sanmartin Josune , de Pablo-Maiso Lorena , Zapico Jose M. , Ramos Ana , de Pascual-Teresa Beatriz , Martinez Alfredo 
Published: February 2011

Abstract
Matrix metalloproteinases (MMPs) have been implicated in tumor development through enhancement of migration, angiogenesis, and metastasis. Therefore, MMP inhibitors (MMPIs) have been described as potential therapeutic agents for cancer treatment. However, clinical development of most MMPIs has been discontinued because of safety reasons due to their low specificity. The design of new MMPIs should pursue not only MMP blockade, but also preserving natural physiological processes that may be jeopardized by inhibition of the wrong class of MMPs. After prolonged research, only MMP1, 2, and 7 have been experimentally validated as cancer targets. On the other hand, reduction of some MMPs such as MMP3, 8, and 9 could enhance tumorigenesis and metastasis, so their inhibition should be avoided.
We describe here the activity of several novel MMPIs generated by computer assisted design and chemical synthesis that present a better inhibitory profile than previous compounds.
Inhibition of MMP2 and 9 activity by increasing concentrations of MMPIs was measured by gelatin zymography using human serum as the source of MMPs. The small molecules were added to the digestion buffer during an overnight incubation and zymogram bands were analyzed by densitometry. Their inhibitory activity was compared to the one elicited by 2R-[(4-biphenylsulfonyl)amino]-N-hydroxy-3-phenylpropinamide (BiPS), a commercially available MMP2/9 inhibitor. Our results show that some molecules inhibit MMP activity more strongly than BiPS, with an IC50 in the picomolar range. Specific MMP2 IC50 values of several of these small molecules were lower than the corresponding values for MMP9, presenting a promising MMP2/MMP9 inhibition ratio.
These inhibitors may be the basis for future therapeutic intervention strategies in cancer.CompoundIC50 MMP2 (pM)IC50 MMP9 (pM)RATIO MMP9/MMP2Zr208741.921097.831.48Zr224&gt;5.00*103&gt;50.00*103-Zr2689.4751.475.44Zr3371.5414.879.67Zr3502.4511.114.53Zr3667.7513.571.75Zr36710.0232.693.26Zr3681.9114.637.67Zr369325.511549.144.76
Calculated IC50 concentrations for MMP2 and MMP9 for several novel molecules
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1553.
Abstract 1555: In vitro and in vivo evaluation of analogs of N-(o-carboxybenzoyl)glutamic acid imide, an active thalidomide metabolite
Authors: Pather Kaveshree , Helsby Nuala A. , Palmer Brian D. , Ching Lai-Ming 
Published: February 2011

Abstract
Thalidomide, with its ability to inhibit angiogenesis and to inhibit the production of survival factors in the bone marrow, has proven to be very effective for the treatment of multiple myeloma. Previous studies from our laboratory identified 3 metabolites in the blood and urine of myeloma patients who were responding to thalidomide therapy (Lu et al, Clin Cancer Res. 9, 1680; 2003). One hydrolysis product, N-(O-carboxybenzoyl)glutamic acid imide (CGI) was as potent as lenalidomide in inhibiting angiogenesis and in inhibiting cytokine production in vitro. Structurally related molecules of CGI have been synthesised in an effort to produce analogs with improved potency, stability and activity. Analogs were each tested for activity for inhibition of tube formation by endothelial cells on matrigel and for inhibition of IL-6 production by RPMI-8226 myeloma cells stimulated by lipopolysacharide (LPS). Analogs with significantly improved potency compared to CGI in inhibiting tube formation and with less cytotoxicity have been synthesized. A tetra-fluorinated analog (SN 29900) was 17-fold and a morpholide-analog (SN 31721) was 8-fold more potent than CGI. SN 29900 was also better in inhibiting LPS-induced IL-6 production by RPMI-8226 cells provided 50% inhibition whilst SN 31721 provided only 15% inhibition at 10 µg/ml. SN 31721 and SN 29900 were both more stable than CGI at low pH levels. These analogs were well-tolerated in mice, with no signs of toxicity seen after an intra-peritoneal dose of 1000 mg/kg. Nor were toxicities observed following daily gavage at 200 mg/kg for 30 days. Plasma pharmacokinetics of SN 29900 and SN 31721 after an intra-peritoneal injection of 100 mg/kg was measured and the results indicated that the analogs were absorbed and cleared more rapidly than lenalidomide. The AUC0-∞ for SN 29900 and SN 31721 in mice was 41.1 µM.h and 162 µM.h respectively compared to 338 µM.h for lenalidomide at the same dose. Lenalidomide potentiates the activity of DMXAA, a vascular disrupting agent in phase III trials, against subcutaneous murine tumours. This was not observed with SN 29900, perhaps because of its poorer pharmacokinetic profile. Development of more lipophilic analogs that may have slower rates of clearance and improved pharmacokinetics are currently under development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1555.
Abstract 1557: Corticorelin acetate exhibits preclinical antitumor activity, alone and with bevacizumab, against human brain tumor models
Authors: Gamez Maria I. , Ryan Robert P. , Keir Stephen T. 
Published: February 2011

Abstract
Corticorelin acetate is a synthetic form of corticotropin-releasing factor undergoing clinical trials in the treatment of peritumoral brain edema. We investigated preclinically its potential as an antitumor agent against orthotopically implanted human brain tumors, and its ability to enhance the therapeutic activity of bevacizumab in one of these models.
Intracranial (ic) tumor transplantation into the right cerebrum was performed using two patient-derived human tumor xenografts: D-341MED pediatric medulloblastoma and D-456MG pediatric multiforme glioblastoma. Mice were randomized 3 days after ic tumor implantation at which time all treatments were begun. Corticorelin acetate was administered at 0.1 and/or 0.2 mg mg/kg/dose, sc, twice daily (bid) depending upon the experiment. Bevacizumab was administered at a dose of 5 mg/kg/day, intraperitoneally (ip), twice weekly. Treatments were continued until a median day of death was reached for each group. In both studies antitumor effects were evaluated based on a survival analysis (Kaplan-Meier).
In the D-341MED, comparing treatments vs control, the low dose corticorelin acetate produced a 56% increase in life span (ILS) (p&lt;0.001); the higher dose of corticorelin acetate yielded a 20% ILS which was also statistically different than the control group (p&lt;0.05). In the D-456MG ic-implanted tumor experiment, corticorelin acetate (0.2 mg/kg/dose, bid, sc) achieved a 42% ILS (p&lt;0.001) while bevacizumab produced a 64% ILS (p&lt;0.001). When the two drugs on these same regimens were applied in combination, the resulting ILS of 92% (p&lt;0.001 versus control) represented a therapeutic enhancement that was statistically different (p&lt;0.05) from either solo drug treatment.
Conclusion: Corticorelin acetate significantly increased the lifespan of mice implanted orthotopically with two different pediatric brain tumor models. In the D-456MG model, in which corticorelin acetate and bevacizumab were evaluated, the combination produced a therapeutic outcome superior to that found using either of the two agents alone.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1557.