bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1929: Antifolates as folate receptor targeting ligands: Design and synthesis of their conjugates with cytotoxic agents
Authors: Vlahov Iontcho , You Fei , Dorton Ryan , Westrick Elaine , Reddy Joseph , Leamon Christopher P. 
Published: August 2012

Abstract
Antifolates are interfering specifically with DNA synthesis in the S-phase of the cell cycle. Thus, they are cytotoxic to rapidly dividing cancer cells, which replicate their DNA more frequently. Some antifolates bind with high affinity to the cell-membrane-associated folate receptor (FR). FR is frequently over-expressed in some of the most prevalent tumors. FR-binding antifolates can also be used as ligands for FR-targeted delivery of therapeutic agents. With this presentation we are reporting an improved synthesis of the FR-binding antifolate CB3717. Furthermore, to demonstrate its dual utility as FR-ligand and therapeutic agent, we designed and synthesized a conjugate of CB3717 with the highly cytotoxic agent Desacetylvinblastine Monohydrazide. A hydrophilic spacer unit and two biologically releasable disulfide-based linker systems were used to construct the conjugate. This conjugate exhibited high binding affinity for FR and excellent anti-tumor activity in vivo (subcutaneous FR+ KB tumors).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1929. doi:1538-7445.AM2012-1929
Abstract 1937: APE/Ref-1, a drugable target for the therapy of human melanoma
Authors: Yang Sun , Zheng Zhonghui , Misner Bobbye , Chamberlin Richard , Meyskens Frank L. 
Published: August 2012

Abstract
Human malignant melanoma exhibits impaired redox status and abnormal redox-regulated signal pathways. Induced as an adaptive response to reactive oxygen species (ROS) and reactive nitrogen species (RNS), a multi-functional protein called APE/Ref-1 serves as a redox chaperone and modulator of many nuclear transcription factors and for maintaining intracellular redox status. Our previous studies showed that knockdown of APE/Ref-1 significantly sensitized melanoma cells to chemo-treatment and reduced metastatic potential markedly. In this study, we further characterized the role of APE/Ref-1 in the invasive properties of human melanoma. Two function-deficient Ref-1 constructs were stably transfected into melanoma cells; further studies with Scratch Migration and Matrigel assays showed that both ΔNLS-Ref-1 and RedoxD-Ref-1 markedly decreased migration and invasive c-apacity. Matrix metalloproteinase (MMP)-1 mRNA levels were also significantly reduced in transfectants, which was reversed by APE/Ref-1 cDNA overexpression. Nitric oxide (NO) stress induced by DETA (NO donor) treatment was associated with enhanced invasion potential of melanoma cells, which was significantly reversed by APE/Ref-1 depletion. These results suggest that specific and potent inhibitors targeting redox activity of APE/Ref-1 should be explored for therapeutic potential. Utilizing 3-dimensional modeling and virtual docking, we have screened compounds from 35 chemical vendors with total number of more than 7 million. Through extensive chemical modifications of our top ranked candidates, we have successfully synthesized novel APE/Ref-1 inhibitors (#598-5, #598-21, and #598-24) showing significant inhibition on the redox activity of APE/Ref-1. Notably, #598-21 exhibited promising anti-melanoma activities with IC50 below 1 μM. In addition, our studies have also identified two leading compounds whose mechanism of inactivation of APE/Ref-1 is due to the oxidation of APE/Ref-1 protein itself. Taking these molecules as lead compounds, we are evaluating their in vivo anti-tumor efficacies and synthesizing more potent inhibitors with enhanced activities.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1937. doi:1538-7445.AM2012-1937
Abstract 194: MicroRNA-1 induces apoptosis by targeting prothymosin alpha in nasopharyngeal carcinoma cells
Authors: Wu Cheng-Der , Kuo Yuan-Sung , Wu Han-Chung , Lin Chin-Tarng 
Published: August 2012

Abstract
MiR-1 (microRNA-1) can be used as a positive control and for optimizing transfection conditions in microRNA experiments (e.g., Ambion Pre-miR miRNA Starter Kit, QIAGEN Syn-hsa-miR-1 miScript miRNA mimic positive control). We noticed that transfection of nasopharyngeal carcinoma cells with miR-1 reveals a typical apoptotic process when observed by time-lapse microscopy. Annexin V and TUNEL staining and caspase assay confirm that miR-1 induces nasopharyngeal carcinoma cell apoptosis. MiR-1 transfection of HeLa, Cal-27, KYSE30 and NPC-TW06 cell lines which express low levels of endogenous miR-1 also induces apoptosis. However, miR-1 transfection of cell lines such as SW620, HepG2, HEK-293T, SAS and PC-13 which express high levels of endogenous miR-1 does not induce apoptosis. To determine miR-1 target genes that are involved in apoptosis, we analyzed microRNA and pathway databases, and cDNA expression microarrays from miR-1 transfected cells. Using qRT-PCR analysis and luciferase reporter vector assays, we found that miR-1 directly targets PTMA (prothymosin alpha). We used PTMA siRNA to down regulate PTMA mRNA levels and observed whether PTMA siRNA could induce apoptosis. Knocking down PTMA expression alone did not induce apoptosis but could accelerate apoptotic progression in cells treated with apoptosis inducers. We also found that transfection of miR-1 could up regulated some pro-apoptotic proteins (HTRA, SMAC, p53, TNF-R1, TNF-R2, TRAILR-1, TNF-alpha, TNF-beta). They are not miR-1 directly target genes but involve in miR-1 inducing apoptosis. We conclude that miR-1 can induced apoptosis in low levels of endogenous miR-1 cell lines. This is a novel model of microRNA-induced cell apoptosis. The apoptotic inducers including actinomycin D, camptothecin and etoposide are also the chemotherapeutic drugs in clinical cancer therapy and PTMA siRNA can accelerate apoptotic progression in cells treated with those apoptosis inducers. Therefore PTMA siRNA may have potential applications as an adjuvant in cancer chemotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 194. doi:1538-7445.AM2012-194
Abstract 1941: Development of novel NSAID conjugated molecules for lung cancer therapy
Authors: Chan Daniel C. , Gera Lajos , Zhang Zhiyong , Zheng Di , Hodges Robert , Stewart John , Bunn Paul 
Published: August 2012

Abstract
Background: Many promising chemopreventive Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) such as Flurbiprofen have acquired anti-cyclooxygenase 2 (COX2) effects with anti-cancer activities. Recently several phosphorylated-NSAID compounds were shown to improve the therapeutic potency over the parental NSAID molecules (JPET 111.183533, 2011) by 10 to 30 folds. Previously, we also reported several novel and potent molecules by the incorporation of NSAIDs such as aspirin, indomethancin, ketorolac, ketoprofen, and sulindac into the aclyting N-terminal of our lead mimetic molecules B317 (F5C-OC2Y-Atmp) (AACR 45: 476, 2004). Here we report a new series of highly potent molecules by replacing the N-terminal F5C with a flurbiprofen (Fbp). The resultant molecules effectively inhibit many cancer cell lines in vitro and in vivo, with efficacy much better than the unmodified parental NSAID molecules or those phosphorylated NSAID analogs. Methods: Standard MTT assays were used to access growth inhibitory effects of the parental and NSAID conjugated molecules. Effects of drugs on cell cycle and apoptosis were analyzed by flow cytometry. In vivo efficacy was evaluated in subcutaneous lung xenografts in athymic nude mice. Results: 32 lung cancer cell lines including 24 NSCLC and 8 SCLC cell lines were treated with various concentrations of some selected conjugated drugs for 4 days. The best compound had an average IC 50 value of 0.5 uM, with a range of 0.1 to 2 uM, while parental Flurbiprofen had IC50 value of 500 uM, with a range of 200 uM to 800uM. Cell cycle analysis showed that exposure of lung cancer cells to these new conjugates resulted in a significant shift of cells from S and G2 phases into G1 arrest, resulting in high percentage of apoptotic cell deaths in a dose- and time-dependent manner. Finally, our in vivo efficacy studies demonstrated that new NSAID conjugates at 5 mg/kg by daily ip injections significantly suppressed growth of subcutaneous xenografts of human lung adenocarcinoma in athymic nude mice without causing weight loss. Conclusion: Our new NSAID conjugate is a novel class of therapeutic agent with anti-growth effects against lung cancer cells in vitro and in vivo, with a 1000 fold increase in potency than the parental Flurbiprofen.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1941. doi:1538-7445.AM2012-1941
Abstract 1949: Receptor mediated delivery of therapeutic Fe3O4 core TiO2 shell nanoparticles
Authors: Yuan Ye , Liu William C. , Wu Aiguo , Paunesku Tatjana , Woloschak Gayle E. 
Published: August 2012

Abstract
Our goal is to target the delivery of therapeutic nanoparticles (NPs) composed of an Fe3O4 core and a TiO2 shell (Fe@Ti NPs) to specific cancer cells and to the appropriate organelles within these cells. Controlled delivery of these therapeutic NPs could lead to the development of more effective therapies for individual types of cancer. In order to control the delivery of these Fe@Ti NPs, we have attached a small peptide that can bind Epidermal Growth Factor Receptor (EGFR) to the TiO2 molecules at the surface of the NPs. EGFR is an ideal target because it is overexpressed in epithelial type cancers, can induce its own endocytosis, and can translocate to the nucleus. We hypothesize that Fe@Ti NPs conjugated with these peptides (Fe@Ti NCs) will be able to bind EGFR resulting in improved internalization and nuclear localization of these NCs by EGFR positive cancer cells. In fact, we have shown that these NCs can indeed bind and extract EGFR from cancer cell protein extracts. Furthermore, we have shown by Flow Cytometry that EGFR positive cancer cells internalize EGFR binding Fe@Ti NCs to a greater degree than NCs displaying a scrambled peptide or bare NPs. Finally, recent experiments utilizing X-ray Fluorescence Microscopy (XFM) indicate that these EGFR binding NCs but not bare NPs can cluster with EGFR at the surface of cancer cells as well as within the cell nucleus.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1949. doi:1538-7445.AM2012-1949
Abstract 1951: Targeting cancer by a chimeric nanoparticle formulation of Cisplatin and PI828, a PI3 kinase inhibitor
Authors: Roy Bhaskar , Sengupta Poulomi , Dinulescu Daniela , Muto Katherine , Papa Anne Laure , Basu Sudipta , Sengupta Shiladitya 
Published: August 2012

Abstract
Combination chemotherapy is the mainstay of cancer regimes. However, additive off target effect of the drugs is still a major drawback of combination therapy. Nanoscale drug delivery systems, through enhanced permeation and retention effect, target the tumour more efficiently while reducing side effects. Combination of Cisplatin, a widely used platinum based chemotherapeutic with PI3 kinase/mTOR inhibitor has shown synergism. In this study, we designed a chimeric nanoparticle of Cisplatin and PI828, a PI3 kinase inhibitor. PI828 was chemically conjugated to cholesterol by a carbamate linkage. Cisplatin was coordinated to a cholesterol-succinic acid derivative via a unique monocarboxylato and OαPt bond. The chimeric nanoparticle was formulated by mixing both the conjugates in definite proportions with phosphatidylcholine and DSPE-PEG. The chimeric naoparticle had a consistent size between 100 to 130 nm determined by dynamic light scattering. The in vitro release kinetics experiment showed slow and sustained release of both the drugs over a time period of 96 hours. In vitro cell proliferation assay expressed cytotoxicity of the chimeric nanoformulation in 4T1, a murine breast cancer cell line and in KRAS upregulated and PTEN suppressed ovarian cancer model cells. We have evaluated the activity of chimeric nanoparticle in a K-Ras(LSL/+)/PTEN(fl/fl) ovarian cancer model, with a luciferase reporter system. The mice treated with chimeric nanoparticle exhibited suppressed tumour growth as well as reduced toxicity as compared to the free drug combination and vehicle treated mice. These results indicate that chimeric nanoformulation can better the outcome of Cisplatin and PI828 combination.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1951. doi:1538-7445.AM2012-1951
Abstract 1952: Targeting the CCL2/CCR2 chemokine pathway in breast tumors through intratumoral delivery of calcium cross linked TAT peptide: siRNA complexes
Authors: Fang Wei Bin , Berkland Corey , Cheng Nikki 
Published: August 2012

Abstract
Breast tumors exhibit inflammatory responses through recruitment of stromal cells in the primary tumor microenvironment, including fibroblasts and macrophages. Accumulation of these stromal cells correlates with development of invasive breast cancer and poor patient prognosis. These stromal cells express high levels of the inflammatory chemokine CCL2, corresponding to overexpression of its receptor CCR2 in the tumor epithelium. Our laboratory and others have shown that CCL2/CCR2 signaling mediates stromal: tumor interactions to regulate breast cancer cell survival, invasion and metastasis. While the CCL2/CCR2 signaling represents a novel and potentially effective therapeutic target in invasive breast cancer, it is necessary to develop new tools to specifically inhibit CCL2/CCR2 signaling in vivo. siRNA knockdown could specifically target CCL2 or CCR2, but is unstable and toxic when delivered in vivo. The HIV-1 derived TAT peptide penetrates cell plasma membranes at high efficiency and contains nuclear translocation signals to enhance siRNA delivery to the nucleus. Recent studies from our research team have shown that CaCl2 condenses TAT/nucleic acids to nanoparticles facilitating cellular uptake. The goals of these studies are to design TAT nanoparticle formulas to target CCL2 and CCR2 protein expression in breast tumors. Using an in vitro luciferase reporter system, we identified specific N/P ratios and CaCl2 concentrations that would transfect stromal cells and PyVmT mammary tumor cells. TAT/CaCl2 nanocomplexes carrying GFP plasmid or Cy3 labeled siRNAs were then injected into PyVmT mammary tumors. We observed visible GFP expression and Cy3 labeled siRNA uptake in over 50% of the PyVmT mammary tumor at low and high N/P ratios. Normal mammary tissues did not show significant uptake of TAT nanoparticles. Flow cytometry analysis showed that high N/P ratios resulted in efficient TAT/CaCl2/siRNA uptake in breast cancer associated fibroblasts and macrophages. TAT/CaCl2/siRNA nanocomplexes formed at low N/P ratios resulted in efficient siRNA uptake in tumor epithelial cells. Preliminary studies of PyVmT mammary tumors showed a reduction in CCL2 and CCR2 expression upon delivery of TAT/CaCl2 nanoparticles carrying CCL2 or CCR2 siRNAs. These data indicate this nanoparticle strategy represents a novel, feasible approach to target the CCL2/CCR2 signaling in breast cancer, with important implications on therapeutic targeting.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1952. doi:1538-7445.AM2012-1952
Abstract 1956: Folate coated platinum nanoparticles: An effective strategy for targeting cancer therapy
Authors: Schneider Evan , Chavali Manideep , Collazo Lourdes , Mironova Tatsiana , Rafailovich Miriam 
Published: August 2012

Abstract
PURPOSE: Platinum nanoparticles (Pt-NPs) are directly toxic to cancer, but also to normal cells. The purpose of this project is to demonstrate that Pt-NPs can selectively kill cancer cells by targeting their delivery through the folate receptor, the expression of which is greatly increased on cancer compared with normal cells. METHODS: Folate coated Pt-NPs were synthesized and used to treat normal (MC-3T3-E1) and malignant (ROS 17/2.8) bone cells in tissue culture. The Pt-NPs were characterized using transmission electron microscopy and zeta potential analysis, which indicated that they had a diameter of 3.5 ± 0.6 nm and were negatively charged. The effects of dose titrated NP preparations and controls, including the addition of free folate, were examined by optical, confocal and transmission electron microscopy. Cell counts were performed using a hemocytometer. RESULTS: Folate coated Pt-NPs were exquisitely toxic to both MC-3T3-E1 and ROS 17/2.8 cell lines causing 100% lethality in the initially tested concentration range (130 - 260 ug/mL). Dose dependent toxicity for both cell lines was evident at lower folate coated Pt-NP concentrations (2 - 22 ug/mL). At the lowest concentrations examined (&lt;5.15 ug/mL), optical microscopy demonstrated selective delivery of the Pt-NPs to malignant ROS 17/2.8 cells as compared with normal MC-3T3-E1 cells. At these concentrations, selective toxicity to the ROS 17/2.8 cells was also demonstrated by confocal microscopic examination of actin elongation and cell alignment patterns as well as direct measures of cell survival. With prolonged exposure to folate coated Pt-NPs at 3.2 ug/mL, 98.5% of normal MC-3T3-E1 cells survived compared with just 32.8% survival of malignant ROS 17/2.8 cells (p &lt; 0.0001). Consistent with the postulated mechanism of folate coated Pt-NP cell entry via the folate receptor, all toxic effects of folate coated Pt-NPs (at 3.2 ug/mL) were completely eliminated by the addition of high doses (10x normal) of free folate, postulated to saturate folate receptor binding sites. CONCLUSION: Folate coated Pt-NPs can be used to directly and selectively kill cancer cells by targeting their delivery through the folate receptor. To our knowledge, this is the first report to demonstrate that targeting a functionally over-expressed cancer cell receptor with its natural ligand linked to toxic NPs can impart selective cancer cytotoxicity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1956. doi:1538-7445.AM2012-1956
Abstract 1957: Targeted polymer-based nanoparticles containing camptothecin: Development and function
Authors: Han Han , Davis Mark E. 
Published: August 2012

Abstract
Camptothecin (CPT) is a naturally occurring broad range anti-cancer alkaloid that acts by inhibiting DNA enzyme topoisomerase I and HIF-1α activities. However, its systemic delivery has been problematic due to its low solubility and toxicity. To this end, we have designed a CPT delivery system that increases the solubility of CPT by more than three orders of magnitude and is capable of directing CPT specifically to cancerous cells. This delivery system is composed of CPT conjugated to a copolymer of mucic acid and poly(ethylene glycol) (MAP). When this conjugate is placed in water it self-assembles into MAP-CPT nanoparticles. The polyol containing backbone of MAP is able to form reversible covalent bonds with boronic acids (BA). Targeting can therefore be achieved through using BA as the linker between the targeting agent and MAP-CPT nanoparticles. MAP-CPT nanoparticles with varying MAP lengths of 20kDa, 65kDa and 100kDa and BA linkers with different binding constants to MAP-CPT nanoparticles are synthesized and characterized. Particle sizes of 40nm in diameter are observed by dynamic light scattering and visualized by particle tracking methods (Nanosight) and cryo-transmission electron microscopy. This particle size takes advantage of the accumulation of nanoscaled entities in tumor tissue via enhanced permeability and retention (EPR) effect. In addition, the slightly negative particle surface charge of −1mV reduces clearance by the reticuloendothelial system (RES) and minimizes undesirable interaction with blood components. A prolonged pharmacokinetic (PK) profile of MAP-CPT system is observed in Balb/C mice with greater than 10% of injected dose remaining in circulation 24 hours post injection for MAP-CPT nanoparticles containing 65kDa or 100kDa MAP. Maximum tolerable dose (MTD) for MAP-CPT nanoparticles containing MAP at 20kDa, 65kDa and 100kDa are found to be 20, 10 and 8mg of CPT/kg respectively in nude mice. Initial anti-tumor data using MAP-CPT nanoparticles in A/J mice bearing Neuro2A (mice neuroblastoma) tumors show tumor regression after two weekly doses of MAP-CPT nanoparticles. We are currently investigating a targeted version of the MAP-CPT nanoparticles through anti-tumor studies comparing targeted (using Herceptin antibodies) versus non-targeted efficacy in nude mice bearing BT-474 (HER2 over-expressing human breast carcinoma) tumors. MAP-CPT, a delivery system for the small hydrophobic drug CPT, is developed and has favorable particle size and surface charge properties, prolonged PK profile and targeting potential. Efforts to define the relationships between targeted and non-targeted versions of the MAP-CPT nanoparticles are in progress.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1957. doi:1538-7445.AM2012-1957