bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A35: Immunological characterization of Imprime PGG® and an anti-EGFR antibody combination treatment for cancer
Authors: Antonysamy Mary A. , Dudney Christine , Yokoyama Yumi 
Published: June 2012

Abstract
More promising antitumor strategies utilize combination therapies, with each strategy targeting a separate aspect of oncogenesis. Imprime PGG® (Imprime PGG) is a soluble beta-1,3/1,6 glucose polymer being developed as an adjunct to monoclonal antibody (MAb) therapy for cancer. Imprime PGG, a pathogen- associated molecular pattern isolated from the cell wall of S. cerevisiae, has shown therapeutic antitumor and survival-enhancing effects when combined with an antitumor MAb in several in vivo syngeneic and xenogeneic tumor models. Here, we evaluated and characterized the antitumor activity and functional synergy of Imprime PGG in combination with an anti-EGFR MAb, cetuximab, in two different cancers, using an EGFR+ human pancreatic tumor line, MiaPaCa-2, and an EGFR+ human ovarian tumor line, SKOV-3. The objectives of this study were: (1) Evaluate the ability of cetuximab to activate complement as measured by iC3b opsonization on tumor cells (measured by flow cytometry using a FITC anti-human iC3b MAb); (2) Characterize tumor cells for expression of the complement regulatory proteins (CRP) CD46, CD55 and CD59 (measured by flow cytometry using fluorescently-labeled CRP-specific antibodies); (3) Evaluate tumor cytolysis following treatment with cetuximab +/- Imprime PGG in the absence and presence of human peripheral blood mononuclear cells (PBMC) (using the MTT colorimetric assay); and (4) Assess the ability of cetuximab +/- Imprime PGG to induce cytokines when tumor cells were cultured with human PBMC. Key findings include: (1) in vitro cetuximab does not induce iC3b deposition on SKOV-3 and MiaPaCa-2 tumor cells over that seen with fresh serum alone. (2) Both tumor cell lines expressed all CRPs but each to a variable extent. (3) Cetuximab did not induce CDC but did induce ADCC in the presence of PBMC, and Imprime PGG further enhanced cetuximab-induced cytolysis under these conditions. (4) The combination of cetuximab and Imprime PGG inhibited the secretion of VEGF in tumor cell/PBMC co-cultures compared to levels observed with either agent alone. These studies demonstrate antitumor synergy of Imprime PGG when combined with cetuximab that may be mediated by modulation of the tumor microenvironment. Overall, the data indicate synergy between Imprime PGG and cetuximab in vitro in inducing antitumor activity in both pancreatic and ovarian tumor cells and provide rationale for such combination strategy for therapy in cancer.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A35.
Abstract A37: Efficacy of combining a novel Aurora kinase inhibitor with radiotherapy in orthotopic liver tumor model of hepatocellular carcinoma
Authors: Cheng Jason Chia-Hsien , Lin Zhong-Zhe , Chia-Hung Chou , Cheng Ann-Lii 
Published: June 2012

Abstract
Radiotherapy is one of the treatment options for hepatocellular carcinoma (HCC), but the unsatisfactory results are mainly due to insufficient dose to the tumor from hepatic intolerance. As compared to advanced technology of radiotherapy, the experience in the combined use of the effective molecular target and radiotherapy remains limited. This study was aimed to assess the effect of combining a novel Aurora kinase inhibitor, VE465, with radiotherapy, by testing the in vitro and in vivo models of human HCC. Human HCC cell line Huh-7, was treated with combined irradiation and the low- toxic dose of VE465. A significant effect on enhancing the radiation induced cell death was found in clonogenic assay. VE-465 induced proliferation blockade, histone H3 (Ser10) dephosphorylation, mitotic disturbance, and apoptosis in Huh-7 cells. The in vivo efficacy of combining VE465 with radiotherapy was investigated in the ectopic xenograft subcutaneous tumor and orthotopic liver tumor models of severe combined immunodeficient mice. Pretreatment with daily i.p. administration of VE465 (20 mg/kg) significantly enhanced the therapeutic effect of radiotherapy (5 Gy per day for 5 days) on Huh-7 derived ectopic xenograft tumor model by 54%. This differential tumor suppression correlated with the modulation of intratumoral biomarker stainings associated with histone 3 phosphorylation inhibition and apoptosis regulation. Furthermore, VE465 improved intrahepatic tumor control and survival of radiotherapy (4 Gy per day for 5 days) treated Huh-7 derived orthotopic liver tumor model by 17.2%, reduction in tumor size. The synergistic effect of combining VE465 with radiotherapy in HCC was associated with histone3 phosphorylation inhibition and cell cycle regulation. We conclude that VE465 is a potent inhibitor of Aurora kinase with clinical value in therapeutic strategies for radiotherapy to HCC.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A37.
Abstract A38: Therapeutic effect of epigallocatechin-3-gallate and silibinin on ATM dynamics in prostate cancer cell line LNCaP
Authors: Farooqi A. A. , Rashid Sadia , Mashadi Taskeen M. , Bhatti Shahzad , Saleem M. 
Published: June 2012

Abstract
Epigallocatechin-3-gallate (EGCG) is a major ingredient of green tea (GT) and silibinin, the active component of silymarin presumably hold a potential to prevent pathogenomics. Prostate cancer exacerbation is triggered by fusion transcripts formed because of genomic instability induced by juxtapositioning of two genes. An abolished ATM dynamics challenges integrity of DNA. In agreement with this assumption ATM and ATR were impaired in LNCaP cell line to confirm a tight interaction of ATM and ATR with the expression profile of TMPRSS2-ERG. Abolished ATM enhanced the expression of the fusion transcript. Similarly blunting of ATR downregulated the expression the fusion transcript giving a notion that ATR is involved in the chromosomal translocation. LNCaP cell lines were analyzed for the effect of EGCG and silibinin on the expression profile of TMPRSS2- ERG. In this particular study treatment of the LNCaP cell line with EGCG and Silibilin recapitulated ATM expression and activity and downregulated the fusion transcript expression. These results underscore the therapeutic effect of EGCG and SB in attenuating the exacerbation of the disease.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A38.
Abstract A4: Withaferin A induces apoptosis in imatinib-resistant CML cells by repressing the Akt signaling pathway
Authors: Chen Ching-Yi , Hung Wen-Chun 
Published: June 2012

Abstract
Although imatinib therapy of chronic myelogenous leukemia is effective, the resistance to imatinib challenges the treatment of this disease. Therefore, search of novel drugs to overcome imatinib resistance is a critical issue in clinic. Withaferin A (WA), an extract of Withania somniferia, exhibits anticancer activity on a number of solid tumors. In this study, we investigate the effect of WA on imatinib-sensitive and -resistant CML cells.
WA at low concentrations induces autophagy in imatinib- sensitive K562 cells. Co-treatment of chloroquine suppresses autophagy and switches WA-treated K562 cells to apoptosis. This data indicates that autophagy protects K562 cells from apoptosis induced by WA. However, we find that WA triggers caspase activation and apoptosis in imatinib-resistant T315I-positive cells and this effect is associated with downregulation of Akt activity. Treatment of the AKT inhibitor LY294002 also causes apoptosis in imatinib-resistant T315I- positive cells. Ectopic expression of constitutively active Akt reverses WA-induced apoptosis and caspase activation in imatinib-resistant T315I-positive cells. Molecular study demonstrates that WA represses the Akt signaling pathway by decreasing Akt expression. We find that WA causes Akt degradation through the ubiquitin- and proteasome-dependent pathway. More importantly, WA also induces AKT downregulation and apoptosis in primary CML cells.
Taken together, our results suggest that imatinib-resistant T315I-positive cells are more addicted to Akt-dependent survival pathway and are more sensitive to WA. Therefore, WA can be useful for the treatment of imatinib-resistant CML.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A4.
Abstract A44: Inhibition of EGFR phosphorylation in a panel of human breast cancer cells correlates with synergistic interactions between gefitinib and 5'-DFUR, the bioactive metabolite of Xeloda®
Authors: Tihyaty Maria Ait , Rachid Zakaria , Jean-Claude Bertrand , Mihalcioiu Catalin 
Published: June 2012

Abstract
The introduction of Xeloda® (capecitabine) in the clinical management of breast cancer has significantly improved survival in patients with mammary carcinoma. It is administered orally and first is metabolized in the liver by carboxylesterases to generate 5'-deoxy- 5-flurocytidine ribose (5'-DFCR), which is subsequently converted to 5'-deoxy-5-fluorouridine ribose (5'-DFUR) by cytidine deaminase. While the latter conversion takes place in tumour and normal tissues, the conversion of 5'-DFUR to the cytotoxic compound 5-FU, occurs principally in the tumour. This reaction is catalyzed by thymidine phosphorylase (TP), which is overexpressed in cancer cells. It has been observed that tumours expressing high levels of TP are the most responsive to capecitabine treatment. Therefore, it was hypothesized that conditions leading to an increase of TP expression could potentiate the action of capecitabine. Our recent studies in a panel of human breast cancer cell lines showed an increase in TP levels upon exposure to gefitinib, an inhibitor of the epidermal growth factor receptor (EGFR). Here, we report on the factors influencing the potency of gefitinib in combination with 5'-DFUR, the bioactive metabolite of capecitabine.
The results showed that: 1) 5'-DFUR activity linearly correlated with TP basal level (R2= 0.808), 2) importantly, the strength of the synergistic interaction between gefitinib and 5'-DFUR, as measured by the combination index at IC50 concentrations (CI50) increased with TP fold changes after gefitinib treatment (R2=0.6449), 3) inversely, it decreased with increasing thymidylate synthase (TS) fold changes after gefitinib treatment (R2=0.6229), 4) moreover, the strength of the synergy correlated with an increase in the proportion of cells arrested in the S and G2M phases of cell cycle (R2=0.6355), 5) changes in TP levels correlated with the magnitude of inhibition of EGFR phosphorylation by gefitinib (R2=0.63) but not with its IC50 values for growth inhibition in the cell panel (R2=0.03611), 6) likewise, DNA damage induced by 5'-DFUR alone or in combination with gefitinib did not correlate with IC50 values for growth inhibition. The results in toto suggest that the observed synergistic interactions between gefitinib and 5'-DFUR may be imputed to molecular events associated with inhibition EGFR phosphorylation and modulation of TP/TS expression in the cells.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A44.
Abstract A47: Possible effect of repetitive magnetic stimulation of the spinal cord on the limb angiogenesis in healthy rats and its clinical implication for the treatment of lymphedema
Authors: Min Yusun , Beom Jaewon , Oh Byung-Mo , Suh Kwan-Sik 
Published: June 2012

Abstract
Objective: To investigate the effect of repetitive magnetic stimulation of the spinal cord on limb angiogenesis in healthy rats and explore its implication for the treatment of lymphedema.
Methods: Twelve adult male Sprague-Dawley rats were divided into four groups as follows: sham repetitive magnetic stimulation (rMS) followed by tissue harvest 5 minutes later (group 1, n=2), 1 Hz rMS and tissue harvest 5 minutes later (group 2, n=3), 20Hz rMS and tissue harvest 5 minutes later (group 3, n=3), 20Hz rMS and tissue harvest 30 minutes later (group 4, n=4). Animals were treated with 20-minute rMS with 120% of the motor threshold on their left side of upper lumbar spinal cord. Expression of angiogenic factors, that is, Akt, phospho-Akt, endothelial nitric oxide synthase (eNOS), phospho-eNOS were measured by Western blot. Bilateral hindlimb muscles (quadriceps and gastrocnemius) were harvested.
Results: Expression of eNOS in quadriceps muscle was markedly increased in group 3 and 4 (6.4 and 7.7-fold each compared with group 1, p=0.04). Also, expression of eNOS in gastrocnemius muscle was increased in group 2 and 3 than in group 1 (p=0.02). Expression of Akt in gastrocnemius muscle tends to increase in rMS- treated groups than in sham rMS group (p&gt;0.05). Expression of phospho-Akt and phospho-eNOS were not comparable between four groups (p&gt;0.05).
Conclusion: Repetitive magnetic stimulation of the spinal cord may exert an angiogenic effect closely linked to lymphangiogenesis. It has clinical implication for the possible therapy of lymphedema caused by breast, cervical or endometrial cancer operation. Future studies with the specific lymphatic endothelial cell markers are required to confirm the effect of repetitive magnetic stimulation on lymphangiogenesis.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A47.
Abstract A48: Demethylating agent 5-Aza-2-deoxycytidine enhances susceptibility of breast cancer cells to anticancer agents
Authors: Mirza Sameer , Sharma Gayatri , Luthra Kalpana , Ralhan Ranju 
Published: June 2012

Abstract
DNA methylation plays an important role in regulation of gene expression and is increasingly being recognized as a determinant of chemosensitivity of human cancers. With the aim of improving the chemotherapeutic efficacy of breast carcinoma, the effect of DNA methyltransferase inhibitor, 5-Aza-2-deoxycytidine (5-aza-CdR), on the chemosensitivity of anticancer drugs was investigated. The cytotoxicity of paclitaxel (PTX), adriamycin (ADR) and 5-fluorouracil (5-FU) was analyzed against human breast cancer cell lines, MDA MB 231 and MCF 7 cell lines using the MTT assay, and the synergy of 5-aza-CdR and these agents was determined by Drewinko's fraction method. The effects of each single agent or the combined treatment on cell cycle arrest were analyzed by flow cytometric analysis. We also investigated the effect of each single agent or the combined treatment of anticancer drugs with 5-aza-CdR on the methylation status of the selected genes by Methylation Specific PCR.
In MDA MB 231 cells a synergistic antiproliferative effect was observed with a combination of 10 µM 5-aza-CdR and these 3 anticancer drugs, while in MCF 7 cells, a semiadditive effect was observed. Treatment with 5-aza-CdR and anticancer drug resulted in partial demethylation of a panel of genes including RAR 2, Slit2, GSTP1 and MGMT.
Based on these findings, we propose that 5-aza-CdR enhances the chemosensitivity of anticancer drugs in breast cancer cells and may be a promising approach for increasing the chemotherapeutic potential of these anticancer agents for more effective management of breast carcinomas.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A48.
Abstract A49: Induction of cell-cycle arrest and apoptosis in MCF7 cancer cells by Newcastle disease virus is associated with upregulation of p21cip and p27kip
Authors: Roslan Nurhidayah , Stanbridge Eric J. , Yusoff Khatijah , Shafee Norazizah 
Published: June 2012

Abstract
Newcastle disease virus (NDV), a member of Paramyxoviridae family, is known for its selective oncogenic effects in cancer cells. NDV infections in cancer cells resulted in cell death through apoptosis. The actual mechanism of this induction has not been thoroughly investigated. Therefore, the objective of the present study is to investigate the effects of infection of a local velogenic strain of NDV, designated as AF2240, on the cell cycle regulation of MCF7 breast cancer cells. Infection was done at a multiplicity of infection of 1, and cell lysates were collected at 3, 6, 9, and 12 hours postinfection. Protein samples were subjected to SDS-PAGE and immunoblotting with antibodies for CDK, CDK inhibitors, and the cyclin family of cell cycle regulatory proteins. Results showed that proteins involved in cell cycle arrest, especially p21cip and p27kip, were significantly increased by 6 hours postinfection. These results suggest that NDV infection leads to initial cell cycle arrest, which is a first step towards cell death through apoptosis, in part via induction of the CDK inhibitors p21cip and p27kip. Findings from this study will provide further understanding of the mechanism of oncolysis by NDV.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A49.
Abstract A5: Lenalidomide inhibits hypoxia-induced HIF-1α production and prevents the invasive phenotype in epithelial solid tumor cells
Authors: Lu Ling , Schafer Peter H. , Bartlett J. Blake 
Published: June 2012

Abstract
Background: In hematological malignancies lenalidomide (len) exerts tumoricidal and immunomodulatory effects and may also influence the tumor cell microenvironment by blocking the proangiogenic and proinvasive effects of growth factors and/or hypoxia. In solid tumor models len is antimetastatic but lacks overt tumoricidal activity. These observations led us to explore the effect of len on hypoxic solid tumor cells, in particular the expression of HIF-α and its upstream regulators p53 and HDM-2.
Methods: Eighteen solid tumor cell lines were tested for the effect of len on the response to hypoxia (1 % O2, 5% CO2, 94% N2; Invivo2 400 hypoxic workstation). Cell lysates from three cell lines (HCT-15, MDA-MB-231 and SKOV-2) were assessed for HIF-1α, p53 and HDM-2 proteins by immunoblot. We also performed immunoprecipitation studies to explore the effect of len on the interaction of these proteins. The effect of len on HIF-1α was assessed in p53 siRNA transfected HCT-15 cells and on HIF-1 α mRNA in transfected Luc-HIF NIH 3T3 cells. Len effects on hypoxia-induced trans-well invasion of three cell lines were also assessed.
Results: Len (1 µM) significantly inhibited hypoxia-induced HIF-1 a protein levels dose-dependently in the majority of tumor cell lines tested; breast (by 68%, MDA-MB-231; 65%, MCF-7), colorectal (76%, HCT-116; 65%, HCT-15; 82% HT-29), ovarian (71%, OVCAR-3; 66%, SKOV-3), renal (83%, 786-O; 57%, HEK293), prostate (54%, DU- 145) and pancreatic (45%, MiaPaca-3)(all p&lt;0.05). Len had no effect on HIF-1 α in SW480 (colorectal), Panc-1, BxPC3 (pancreatic), SW579 (thyroid), NCI-H446 (SCLC) or Caki-1 (Renal) cell lines or on HCT-15 cells transfected with p53 siRNA. In addition to inhibition of HIF-1 α protein len also inhibited hypoxia-induced HIF-1α mRNA expression (p&lt; 0.01). Len enhanced p53 levels in hypoxic HCT-15 cells (by 2-fold; p&lt;0.05), SKOV-3 cells (by 4-fold; p&lt;0.01) and MDA-MB-231 cells (by almost 2-fold; p&lt;0.05) but had little apparent effect on the interaction of these proteins. Len totally inhibited the 2-fold hypoxic induction of HDM-2 levels in HCT-15 (p&lt;0.05) and SKOV-3 (p&lt;0.01) cells but had no effect on HDM-2 in p53 mutant MDA-MB-231 cells. Tumor cell invasiveness was enhanced in response to hypoxia by ~3- fold in all three lines and was blocked by 50-80% by len treatment (all p &lt; 0.05).
Conclusions: These results suggest that len inhibits the proinvasive hypoxic response in multiple, diverse tumor lines and may exert antimetastatic effects within the hypoxic solid tumor microenvironment.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A5.
Abstract A50: Targeting 3-phosphoinositide-dependent kinase-1 and mammalian target of rapamycin synergistically inhibits cell proliferation of breast cancer cells
Authors: Walls Marlena , Baxi Sangita M. , Murphy Sean , Johnson Teddy W. , Tod Smeal , Yin Min-Jean 
Published: June 2012

Abstract
Aberration of receptor tyrosine kinases (RTKs), PTEN (phosphatase and tensin homolog deleted on chromosome 10), and PIK3CA (encodes the p110 subunit of phosphatidylinositol 3-kinase [PI3K]) frequently contribute to tumor progression through their ability to regulate the intracellular level of phosphatidylinositol-3,4,5- triphosphate (PIP3). PIP3 subsequently recruits 3-phosphoinositide- dependent kinase-1 (PDK-1), a serine/threonine kinase, to the plasma membrane and initiates PDK-1 kinase activity to phosphorylate AKT within the activation loop of the catalytic domain at the residue threonine-308 (T308). The mammalian target of rapamycin (mTOR) plays a critical role in the PI3K/AKT pathway. The mTOR kinase is present as two protein complexes, TORC1 and TORC2. The TORC1 complex is activated by PI3K/AKT and phosphorylates p70S6K and 4E-BP1 to modulate protein translation whereas the TORC2 complex phosphorylates AKT in the regulatory domain at residue serine 473 (S473). Phosphorylation of AKT at both T308 and S473 fully activates AKT function through downstream signaling to mediate cell proliferation, survival, migration, angiogenesis and other pathways which are critical for tumor progression. We have developed a potent and selective PDK1 inhibitor (PF-05177624) that is sufficient to inhibit the phosphorylation of AKT atT308 and block cell proliferation of cancer cells in vitro. In this study, we combined this PDK1 inhibitor (PF-05177624) and a selective mTOR kinase inhibitor (WYE-354) to perform the combination studies in breast cancer cell lines. Our data demonstrate that targeting both PDK1 and mTOR simultaneously produces a synergistic inhibitory effect in AKT phosphorylation. Moreover, this results in a synergistic inhibition of cell proliferation in breast cancer cells. Our data suggest that a combination strategy of targeting both PDK-1 and mTOR may have potential improved clinical efficacy in the development of cancer drugs for breast cancer patients.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A50.
Abstract A53: Lovastatin inhibits EGFR dimerization and AKT activation in squamous cell carcinoma cells: Potential regulation through targeting rho proteins
Authors: Zhao Tong T. , Dimitroulakos Jim 
Published: June 2012

Abstract
We recently demonstrated the ability of lovastatin to inhibit the function of the epidermal growth factor receptor (EGFR) and its downstream signaling of the PI3K/AKT pathway. Combining lovastatin with gefitinib, a potent EGFR inhibitor, induced synergistic cytotoxicity in various tumor-derived cell lines. In this study, lovastatin treatment inhibits ligand-induced EGFR dimerization in squamous cell carcinoma (SCC) cells and its activation of AKT and its downstream targets 4EBP1 and S6K1. This inhibition was associated with global protein translational inhibition demonstrated by a decrease in RNA-associated polysome fractions. The effects of lovastatin on EGFR function were reversed by the addition of the geranylgeranyl pyrophosphate that acts as a protein membrane anchor. Lovastatin treatment induced actin cytoskeletal disorganization and the expression of the geranylgeranylated rho family proteins that regulate the actin cytoskeleton, including rhoA. Lovastatin-induced rhoA was inactive as EGF stimulation failed to activate rhoA and inhibition of the rho-associated kinase, a target and mediator of rhoA function, with Y-27632 also showed inhibitory effects on EGFR dimerization. The ability of lovastatin to inhibit EGFR dimerization is a novel exploitable mechanism regulating this therapeutically relevant target. To assess the potential of this approach, we evaluated the effect of statin use in patients enrolled in the BR21 erlotinib phase III study in non-small cell carcinoma (NSCLC) patients. In the erlotinib arm of this trial, although not statistically significant due to the limited number of patients on statins, in general, patients that were on statins performed better than patients without statins.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):A53.