bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1356: Real-time in vivo color-coded imaging of the interaction between immunocytes and tumor cells during cancer therapy
Authors: Kimura Hiroaki , Hayashi Katsuhiro , Tsuchiya Hiroyuki , Tomita Katsuro , Aki Ryoichi , Kishimoto Hiroyuki , Suetsugu Atsushi , Momiyama Masashi , Bouvet Michael , Hoffman Robert M. 
Published: February 2011

Abstract
We imaged the interaction between osteosarcoma cells and splenocytes using fluorescent proteins during chemotherapy or dendritic-cell (DC) therapy. GFP-expressing splenocytes (5 × 106), derived from GFP transgenic BALB/c mice, were transplanted to BALB/c nude mice. Then, RFP-143B human osteosarcoma cells (5 × 105) were injected in a skin flap raised in these mice. The mice were treated with doxorubicin (5 mg/kg), i.p. three days in a row. The RFP-expressing 143B tumor and the GFP splenocytes accumulation around the tumor were imaged for three days. Dendritic cells (1×106), which were activated with a 143B cells lysate, were injected into the inguinal lymph node of the mice. The tumor grew gradually in the control group, whereas in the chemotherapy group, the tumor became progressively smaller. In the DC group, the tumor regressed and was almost eradicated 12 days after treatment. In the DC group, GFP splenocytes accumulated in large numbers around the tumor three days after DC treatment. The accumulation of DC cells was diminished as the tumor became smaller. In the chemotherapy group, in contrast, accumulation of splenocytes gradually increased even though the tumor became progressively smaller. Future experiments will be on syngeneic models to determine the influence of an intact immune system on the interaction of splenocytes and DC cells with cancer cells.
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 1356.
Abstract 1374: Synthetic heparan sulfate oligosaccharides inhibit endothelial cell functions essential for angiogenesis
Authors: Avizienyte Egle , Cole Claire L. , Hansen Steen U. , Barath Marek , Rushton Graham , Gardiner John M. , Jayson Gordon C. 
Published: February 2011

Abstract
Heparan sulfate (HS), a linear glycosaminoglycan, is an essential structural component required for the activity of numerous angiogenic cytokine-receptor signalling complexes. To exploit the potential of inhibiting HS-dependent signalling complexes we synthesized a series of heparan sulfate oligosaccharides containing up to 12 saccharide residues with variable but defined sulfation patterns. The ability of oligosaccharides to compete with HS in FGF2, VEGF and IL-8 binding significantly increased with the length of oligosaccharides and especially with additional sulfate groups incorporated at specific positions in the hexuronic acid and glucosamine. In this competition assay, oligosaccharides exhibited higher levels of inhibition of FGF2 binding to HS than of VEGF and IL-8 binding to HS. Correspondingly, the inhibitory potential of oligosaccharides against FGF2-, VEGF- and IL-8-mediated endothelial cell responses was greater in longer species of oligosaccharides that bore more sulfate residues. Oligosaccharides inhibited cytokine-induced endothelial cell migration to the same extent as kinase inhibitors targeting FGF receptors or VEGF receptor 2 (VEGFR2). In contrast, FGF2-induced endothelial cell proliferation was only inhibited when cells were treated with an oligosaccharide composed of 12 saccharide residues at a concentration that significantly exceeded that of the FGFR inhibitor suggesting that oligosaccharides mainly interfere with the migration, but not proliferation of endothelial cells. The ability of oligosaccharides to target endothelial cell migration correlated with their ability to ablate FGF2- or VEGF-induced accumulation of activated peripheral FAK-pY397 and actin polymerization at the cell periphery. More importantly, there was a strong correlation between oligosaccharide structure and the level of inhibition of endothelial tube formation. Correlating with the biological activity of oligosaccharides, FGF2- and VEGF-induced downstream signalling events were sensitive to the treatment with biologically active oligosaccharides that specifically reduced FRS2, VEGFR2, ERK1/2 and AKT phosphorylation. In conclusion, we have determined the critical number of HS saccharide residues and sulfation pattern required to inhibit endothelial cell responses to key angiogenic cytokines.
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 1374.
Abstract 1381: The effect of proteasome inhibitor velcade on tumor microenvironment
Authors: He Fuqiu , Sun Xiaorong , Ackerstaff E , Xing Ligang , Minami Akiko , Hsiao Hung Tsung , Carlin Sean , Ling Clifton C. , Koutcher Jason , Li Gloria C. 
Published: February 2011

Abstract
It has been reported that the therapeutic effect of the proteasome inhibitor Velcade is due to its selective interference in the hypoxia pathway. We studied the effect of Velcade on tumor microenvironment and examined the underlying molecular mechanisms. We have generated a human colorectal cancer xenograft model (#C53) in which the hypoxia-inducible dual reporter fusion gene (HSV1-TK and eGFP) was under the control of hypoxia-response-element (HRE). In vitro, #C53 cells were treated with Velcade in normoxic and hypoxic conditions, and the following assays were performed in comparison with controls: eGFP (flow cytometry), CA9 (western blot), VEGF (ELISA), and TK activity (trapping of the marker substrate 14C-FIAU). In vivo, #C53 xenografts were treated with Velcade and various assays performed, including a) Dynamic contrast-enhanced (DCE) MRI pre and post treatment; b) dual hypoxia marker (pimonidazole and EF5) administration pre and post treatment; c) fluorescence microscopy of Hoechst 33342 (perfusion), eGFP, HIF-1α, and CA9; and d) plasma VEGF level (ELISA), Where applicable data from control and treated tumors were compared. Our results showed that in both in vitro and in vivo experiments Velcade treatment increased the level of HIF1α, but decreased those of hypoxia-induced eGFP, TK, CA9 and VEGF. Interestingly, in the dual hypoxia marker study there were significant EF5-positive regions that did not co-localize with pimonidazole-positive regions, suggesting de novo hypoxia and perhaps another novel effect of Velcade on tumor microvasculature. Consistent with these results, DCE MRI demonstrated decrease global tumor blood flow with Velcade treatment. Our data suggest that Velcade suppresses the hypoxia response by disrupting the HIF1 transcriptional activity. In addition, our results suggest a novel function of Velcade in modifying the tumor microenvironment and decreasing tumor perfusion as noninvasively detected by DCE MRI.
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 1381.
Abstract 1385: Fusion protein containing RGD-endostatin and human Fc of IgG4improves anti-angiogenic and anti-tumor activity
Authors: Jing Yawu , Wu Kailang , Lu Huarui , Subramanian Indira V. , Ramakrishnan Sundaram 
Published: February 2011

Abstract
Inhibiting angiogenesis is a promising strategy for cancer therapy. Endostatin, a C-terminal fragment of collagen XV[[Unsupported Character - &#1064;]], is an endogenous inhibitor of angiogenesis. We have earlier shown that addition of integrin-targeting sequences to a mutant endostain (P125A-endo) improved localization to tumor vasculature. In the present study, we investigated whether genetically fusing endostatin to Fc region of human IgG can prolong circulatory half-life and improve anti-tumor activity. Two types of constructs were made: a) RGD-endostatin-Fc and b) Endostatin-RGD-Fc. The location of the RGD moiety was either placed at the NH2-terminus or between the carboxyl terminus of endostatin and Fc. Both constructs were expressed in HEK-293 cells and purified using affinity chromatography. Our results show the biological activity of endostatin was significantly enhanced by linking to the Fc region of IgG when compared to P125A-endostatin expressed in yeast. Both RGD-Endo-Fc and Endo-RGD-Fc were able to bind endothelial cells very efficiently and inhibited endothelial cells proliferation, migration in vitro and angiogenesis in vivo. We then investigated the ability of the fusion protein to inhibit ovarian cancer growth in a xenograft model. Once a week administration of the fusion protein into mice bearing established ovarian tumors inhibited tumor growth and increased their survival. Anti-tumor activity of the fusion protein was comparable to Bevacizumab-mediated suppression of tumor growth. Furthermore, when mice were treated with a combination of the fusion protein and Bevacizumab, more than additive inhibition of tumor growth was observed. These data suggest that fusion with Fc-fragment can improve the anti-angiogenic and anti-tumor activity of endostatin. Moreover, our results support a strategy to combine two anti-angiogenic reagents such as anti-VEGF antibody and endostatin-Fc fusion protein to additively inhibit ovarian cancer growth.
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 1385.
Abstract 139: The identification of potent inhibitor of apoptosis protein (IAP) inhibitors for clinical development
Authors: Morris Stephen J. , Ashdown Helen , Boudreault Alain , Durkin Jon , Gillard John , Hewitt Kim , Jaquith James , Jerome Lori , Laurent Alain , Maltais Stephane , Methot Danielle , Patel Harshila , Romeo Andrea , Devalaraja M , Humphreys R 
Published: February 2011

Abstract
The inhibitor of apoptosis proteins (IAPs) are important regulators of cell death. Over-expression of IAPs, including XIAP, cIAP1 and cIAP2, predicts poor patient outcome in several types of cancer. XIAP binds to and inhibits caspases 3, 7 and 9. Inhibition of IAP function can enhance cell death in tumor cells. Inhibition of IAPs is being explored clinically with XIAP anti-sense (AEG35156) and small molecule inhibitor (HGS1029) strategies.
We describe small molecule inhibitors of the IAPs that have been designed to bind to the homologous BIR3 domains on the IAPs, which is the site of binding of second mitochondria-derived activator of caspase (SMAC). Structure-activity trends of IAP inhibitors were evaluated for binding potency and selectivity towards IAP BIR domains and analyzed for their ability to sensitize cancer cells to death alone or in conjunction with the agonistic TRAIL receptor 1 monoclonal antibody, mapatumumab, or chemotherapeutic agents.
Bridging selected compounds at various sites led to compounds with binding affinities for IAPs in the picomolar range. In cellular assays, IAP inhibitor compounds caused rapid and robust loss of cIAP1, consistent with stimulation of E3 ligase activity. In vitro cytotoxicity assays demonstrated sensitization of tumor cell lines to co-treatment with mapatumumab or chemotherapy at low nanomolar concentrations.
In vitro ADME studies were conducted in multiple species to select stable molecules which were negative in CYP and hERG binding assays. Selected compounds had high protein binding in plasma from multiple species. IV administration in mice resulted in Cmax values in excess of the EC50 required for cancer cell death in vitro.
Efficacy of lead compounds was demonstrated against several xenograft tumor models as single agents and in combination with either mapatumumab or conventional chemotherapeutics. This led to the identification of a highly potent compound series from which a clinical development candidate, HGS1029, was selected.
Solid tumor and lymphoid malignancies Phase 1 cancer trials with HGS1029 have been initiated.
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 139.
Abstract 1392: HEDS selectively radiosensitizes human cancer cells in glucose-deprived environments via inhibition of Ku protein function
Authors: Ward Kathleen M. , Li Jie , Zhang Donglan , Dayanandam Eswarkumar , DeNittis Albert S. , Prendergast George C. , Ayene Iramoudi S. 
Published: February 2011

Abstract
There remains great interest in strategies to increase the efficacy of radiation therapy in cancer patients. Glucose depletion occurs commonly in certain regions of bulky solid tumors, owing to high glucose metabolism combined with poor perfusion caused by a disorganized blood vasculature. Evidence suggests that cancer cells located in glucose-deprived regions are resistant to therapeutic killing. Agents that sensitize glucose-deprived cancer cells might offer useful adjuvants for tumor radiotherapy. In an earlier study, we demonstrated that rodent cells which are genetically deficient in the oxidative pentose phosphate cycle (OPPC) display a heightened response to hydroxyethyldisulfide (HEDS), a thiol-specific oxidant that can radiosensitize cells by blocking the redox-dependent function of DNA repair protein Ku. Since glucose is the chief substrate of the OPPC, and the OPPC is responsible for detoxifying HEDS, we reasoned that glucose deprivation should phenocopy the effects of OPPC deficiency in enhancing radiosensitization by HEDS. To test this prediction, we compared the effects of HEDS treatment in human colon cancer cell lines HCT116 or HT29, which are radiation sensitive or resistant, respectively. In both cell lines, HEDS was detoxified by OPPC-mediated conversion to mercaptoethanol (ME) in high-glucose media but not in low-glucose media. Consistent with the decrease in cellular bioreductant activity by glucose depletion, HEDS greatly decreased free glutathione levels under low-glucose conditions. Similarly, HEDS greatly decreased the free thiol content of total proteins and impaired the Ku DNA binding activity in low-glucose conditions. Most significantly, in clonogenic cell growth assay, the cytotoxic effects of HEDS were greatly increased under low glucose conditions, when added by itself to HCT116 cells but particularly when added in combination with irradiation to HCT116 or HT29 cells. Together, our findings indicate that glucose depletion enhances the ability of HEDS to radiosensitize cancer cells. More broadly, our findings suggest the potential to use HEDS in a novel strategy to enhance killing of radioresistant regions of tumors that are characterized by a glucose-depleted state.
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 1392.
Abstract 1394: Pro-apoptotic and anti-tumorigenic effects of a naturally occurring proteasome inhibitor on hormone-refractory prostate cancer
Authors: Karnak David , Dai Yao , DeSano Jeffrey T. , Tang Wenhua , Ljungman Mats , Lawrence Theodore S. , Xu Liang 
Published: February 2011

Abstract
A major mode by which cancer cells evade death is by an acquired ability to suppress apoptosis. In hormone refractory prostate cancer, the overexpression of pro-survival/anti-apoptotic proteins results in resistance to chemo- and radio-therapy. Hence, developing co-therapies that sensitize cells to standard treatment regimens by overcoming this apoptotic block could improve treatment outcomes in advanced prostate cancer. The naturally occurring proteasome inhibitor celastrol has been previously reported to inhibit DNA damage processing and synergize with radiotherapy to kill PC-3 cells. To further explore the mechanism by which celastrol might potentiate cell death, several lines of questioning were explored. First, the open question regarding whether or not celastrol inhibits DNA damage repair, not simply processing, was tested in the comet assay. The tail moments measured in cells treated with celastrol, irradiated and allowed to recover were significantly greater than those in untreated cells, indicating that DNA damage repair was inhibited. In other experiments, cells treated with celastrol displayed an increased expression of the pro-apoptotic, BH3 only protein Noxa. This correlated with an increase in apoptotic cell death which was further augmented by ionizing radiation treatment. The pro-survival protein NFkB is tightly controlled by IkB-alpha binding. Proteasome inhibition can suppress the pro-survival activity of NFkB by decreasing the turnover of IkB-alpha. Indeed, IkB-alpha was found to accumulate in celastrol treated cells. Further, NFkB target gene activation was markedly reduced. To test the feasibility of celastrol treatment in animals, the PC-3 xenograft model in the athymic nude mouse was employed. When celastrol was combined with radiotherapy, tumor volume decreased, apoptosis increased, angiogenesis decreased, and NFkB target gene mRNA levels were found to be lower. Taken together, these data show that celastrol sensitized PC-3 cells to radiation both in vitro and in vivo by impairing DNA damage repair and augmenting apoptosis through suppressing NFkB activation and increasing the protein levels of Noxa. Celastrol may hold promise as a co-therapy with radiation for the treatment of hormone-refractory prostate 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 1394.
Abstract 1396: FGFR1-induced radioresistance of Panc02 pancreatic tumor cells is decreased by SSR128129 treatment in vitro and in vivo
Authors: Tardy Claudine , Gueguen Genevieve , Mazoyer Sandrine , Morin Gaëlle , Planel Severine , Herbert Corentin , Toulas Christine , Moyal Elisabeth Cohen-Jonathan , Schaeffer Paul , Bono Françoise 
Published: February 2011

Abstract
We have previously established the important role of FGF-2 pathways in tumor cell radioresistance. Although radiotherapy is commonly used in the treatment of pancreatic carcinomas which are known to express FGF and FRGFR, the role of FGFR pathways in radioresistance of pancreatic tumor has not yet been studied. We established a new syngenic mouse model of orthotopic pancreatic xenograft of Panc02 cells transfected with hFGFR1-receptor (Panc02-FGFR1). Whereas the in vitro radioresistance of the parental cell line (Panc02) was not affected by the addition of the specific FGF-receptor antagonist SSR128129, Panc02-FGFR1 radioresistance was significantly decreased by treating cells with SSR128129 (1 µM) 4 hours before irradiation (mean inactivation dose [MID] was 6.1±0.2 Gy in control PancO2-FGFR1 versus 4.2±0.2 Gy in SSR128129 treated cells, P&lt;0.001). Orthotopic injection of Panc02-FGFR1 cells in syngeneic C57B6 mice led to rapid growth of pancreatic tumors. While SSR128129 (30 mg/kg/d) was ineffective on the tumor growth, this compound significantly decreased microvessel density in Panc02-FGFR1 tumors (104.7±14.6 vs 136.6±10.3 vessels/field, P&lt;0.001). Local irradiation (2×2.5 Gy) of tumor-bearing animals previously treated for 1 week with SSR128129, led to a strong decrease of tumor size (40% decrease, P&lt;0.05) one week after radiotherapy, whereas the tumor size of untreated animals was not affected by irradiation. The effect of SSR128129 on microvessel density was not affected by radiotherapy. Together, these data show that inhibiting FGFR pathways leads to a major radiosensitization of pancreatic tumors in vitro and in vivo.
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 1396.
Abstract 1402: Molecular basis for soy isoflavone genistein in the prevention of posttreatment recurrence of neuroblastoma
Authors: Veeraraghavan Jamunarani , Madhusoodhanan Rakhesh , Natarajan Mohan , Herman Terence S. , Aravindan Natarajan 
Published: February 2011

Abstract
Clinical and laboratory evidence suggests that neuroblastoma contain populations of rapidly proliferating clonogens that survive chemoradiation or conventional radiotherapy leading to radioresistance. To that note, radioresistance could be associated with survival advantage resulting in clonal selection and tumor re-growth. Recently, we demonstrated that IR activates NFκB that enhances cell survival by switching on genes that attenuate apoptosis. Coherently, studies have demonstrated Genistein (GEN) inhibits NFκB and radiosensitizes cancer cells. In this study, we investigated the functional mechanistic regulation of NFκB mediated survival advantage and, delineated the efficacy of GEN in this setting. Human SH-SY5Y, IMR-32 and SK-N-MC cells exposed to 2Gy (IR) with or without GEN (100μM) were examined after 15min through 72h. EMSA analysis showed a robust and persistent activation of NFκB at least up to 72h in IR exposed cells. Consistently, IR induced a sustained transactivation (QPCR) and intercellular (ELISA) TNFα in these cells. Forced inhibition of NFκB (SN50, RelA siRNA) or TNFα (TNFR1-Ab) completely and persistently inhibited IR-induced NFκB and/or TNFα demonstrating the IR-induced initiation of NFκB→TNFα→NFκB feed back mechanism (PFC). Consistently, IR simulation experiments with NFκB (SNP, p50/p65 transfection) or TNFα (rH-TNFα) over expression, persistently activated NFκB and/or TNFα exhibiting the occurrence of PFC. Furthermore, IR profoundly induced both mRNA (QPCR) and cellular localization (immunoblotting) of IAP1, IAP2 and Survivin. NFκB knock-out experiments portrait a NFκB dependent activation of IAP1, IAP2 and Survivin in these cells. Conversely, GEN treatment completely and persistently inhibited IR-induced NFκB and, both TNFα transactivation and intercellular levels. Moreover, NFκB and/or TNFα over expression studies with GEN demonstrate the disruption of PFC. In addition, GEN markedly, inhibited IR-induced NFκB dependent IAP1, IAP2 and Survivin and greatly conferred IR-induced inhibition of cell survival. Taken together these results suggests that the surviving neuroblastoma cells may result in the development of survival advantage mediated by persistent activation of NFκB through NFκB→TNFα→NFκB PFC. More importantly, disrupting IR-initiated PFC with GEN may significantly inhibit NFκB dependent survival advantage and, may serve as a potential deliverable in mitigating neuroblastoma relapse and progression after radiotherapy.
Funding Support: ACS- IRG-05-066-01; Presbyterian Health Foundation
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 1402.