bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5459: Antitumor activity of EP80061, a small-glyco drug in preclinical studies
Authors: Nancy-Portebois Vanessa , Cabannes Eric , Petitou Maurice , Serin Guillaume , Mirjolet Jean-François 
Published: February 2011

Abstract
Background:
Heparan sulphate (HS) containing proteoglycans regulate the activity of many proteins (growth factors, cytokines, adhesion molecules…) involved in pathologies like cancer, inflammation, cardiovascular, metabolic and neurodegenerative diseases, as well as in viral infection. HS mimicking oligosaccharides can interfere with protein/HS interactions and thus modulate the resulting biological effects. The optimization of fully synthetic HS mimetics exhibiting anti-tumour and anti-metastatic properties is currently in progress.
Methods:
Compound selection was performed using classical in vitro assays (binding and proliferation) and a cellular angiogenesis assay (Angiokit®).
In vivo, Swiss nude mice subcutaneously (SC) xenografted with A-673 human rhabdomyosarcoma tumor cells were used to compare compounds showing significant anti-tumour activity. Compounds were intraperitonealy (IP) injected on a daily basis. The most potent compound was then evaluated on syngeneic mouse models: C57 BL/6 mice intravenously (IV) injected with B16-F10 malignant melanoma cells and Balb/c mice bearing orthotopic (OT) Renca kidney carcinoma.
Results:
Binding assays to FGF-2, PDGF-BB, VEGF-B and SDF-1α in Biacore experiments and growth factor-dependent proliferation tests led to the identification of several inhibitors. Optimized compounds exhibiting anti-angiogenic activities were selected in Angiokit® assays. EP80061 was selected for further studies on the basis of significant activity in this assay.
In A-673 SC mouse model, EP80061 was also the most powerful compound. When IP injected at 30 mg/kg/inj. for 28 consecutive days, it induced a marked tumour growth delay. At D22, the optimal T/C value (46%) was reached with a significantly lower tumour volume (p=0.0006, 1672 ± 760 and 765 ± 402 mm3 for vehicle and EP80061 treated mice, respectively). EP80061 induced also a very significant decrease in lung metastasis development in B16-F10 IV injected mice treated at 30 mg/kg/inj. (p&lt;0.0001, 92 ± 24 and 12 ± 8 metastases for vehicle and EP80061 treated mice, respectively). Promising results were also obtained on OT Renca bearing mice where EP80061 induced a decrease of OT tumour size.
Conclusion:
Current preclinical results support EP80061 as a lead candidate for further developments of small-glyco drugs as anticancer compounds.
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 5459.
Abstract 5465: Functional and structural characterization of the high-affinity EphA2-binding site of ephrinA1
Authors: Tome Carla M. Lema , Palma Enzo , Wykoski Jill , Debinski Waldemar 
Published: February 2011

Abstract
Glioblastoma multiforme (GBM), a high-grade astrocytoma, is the most common primary brain tumor in adults. GBM is a highly lethal cancer associated with neurological morbidity, and median survival of GBM patients is between 12 to 15 months. Previous work in our laboratory demonstrated that the EphA2 receptor, a tyrosine kinase protein receptor, but not its preferred ligand, ephrinA1, is over expressed in GBM specimens and cell lines, and its expression is linked to malignancy grade and patient survival. Binding of ephrinA1 to EphA2 results in receptor downregulation and internalization, which mediates reversal of malignant properties in GBM cells. Moreover, ectopic expression of ephrinA1 in GBM cells results in its release into the extracellular environment as a soluble, monomeric protein which mediates its effects in a paracrine manner. Thus, we have begun studying the structure-function relationship of ephrinA1 with the goal of developing an optimal soluble ligand for EphA2. The region selected was the GH loop of ephrinA1, a highly conserved region known to mediate high-affinity binding of ephrinA5 to EphA3 and very recently confirmed to mediate ephrinA1 to EphA2 binding. Alanine substitution mutants of all amino acids within the ephrinA1 GH loop (H-108FQRFTPFTLGKEFKE123G-OH) were generated by site-directed mutagenesis. Sequence-verified ephrinA1-mutant plasmids were then transfected into U-251 MG GBM cells. Individual clones were selected and high-expressing clones were further cultured. Mutant ephrinA1 expression in the media was verified by western blotting (WB). Conditioned media (CM) was assayed for ephrinA1 content using a sandwich ELISA. Standardized wild-type and mutant CM was used in subsequent experiments. Functional activity of each mutant was assessed by EphA2 down-regulation in U-251 cells. Alanine substitutions at positions P113 and T115 enhanced, while mutants of ephrinA1 at positions F111, T112, F114, L116, K118, E119, and F120 had a deleterious effect on EphA2 down-regulation when compared to that induced by wild type ephrinA1. In addition, those mutations that enhanced receptor down-regulation also caused dramatic changes in cell morphology in GBM cells within 15 min of treatment. Furthermore, treatment using P113A and T155A CM decreased phosphorylation of ERK within 30 min, indicative of suppression of intracellular signaling survival pathways. Being that ephrinA1 is a tumor-suppressing factor in GBM, finding its optimal genetically engineered variant(s) will have an important impact on the design and production of novel anti-tumor agents. These molecularly-targeted agents will represent a novel approach to GBM treatment.
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 5465.
Abstract 5484: Simultaneous targeting of EGFR and MET pathways using nanotechnology improves the treatment outcomes of photodynamic therapy for pancreatic cancer
Authors: Zheng Lei Z. , Rai Prakash , Mai Zhiming , Spring Bryan Q. , Hasan Tayyaba 
Published: February 2011

Abstract
Pancreatic Cancer (PanCa) is difficult to treat due to its inherent resistance to most therapies. First line chemotherapy only has a 5% response rate that yields a dismal prognosis of 6-month median survival and &lt;4% 5-year survival. Combination therapies only showed modest benefits and there are still vital unmet needs for alternative treatment that improve overall patient survival.
Photodynamic Therapy (PDT), a light-regulated cytotoxic therapy, showed promise as a new treatment modality for PanCa which improved median survival from 6 to 9.5 months in a pilot clinical trial. This result triggered our preclinical development of PDT combination regimen targeting proliferative pathways to further enhance treatment outcome.
Using nanotechnology, we designed and synthesized nano-constructs co-encapsulating multiple therapeutic agents that can simultaneously target EGFR and MET-regulated proliferative pathways in combination with cytotoxic PDT treatment. We tested these nano-constructs in orthotopic pancreatic cancer models for treatment efficacy and our major findings include:
1) The nanoscale multidrug delivery system allows simultaneous targeting of EGFR and MET-regulated proliferative pathways and offered the best reduction of local tumor burden and metastatic burden to lymph nodes, lung and liver. With only one time of treatment, the local tumor burden is reduced to 10% of that of non-treated, and significant reductions of organ metastasis were also achieved.
2) The nanoscale multidrug delivery system delivers PDT agent and MET inhibitor PHA-665752 with higher payload and reduces their systemic toxicity. The EGFR inhibitor Cetuximab is delivered intracellularly into cancer cells, which targets both intracellular and cell surface EGFR. Intracellular delivery of Cetuximab increased treatment efficacy compared to naked Cetuximab.
We are continuing optimizing the scheduling of individual treatments to further improve treatment outcomes.
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 5484.
Abstract 5485: Modular nanotransporters: a chimeric multi-functional platform for drug delivery in vivo
Authors: Sobolev Alexander S. , Slastnikova Tatiana A. , Rosenkranz Andrey A. , Schiffelers Raymond M. , Zalutsky Michael R. 
Published: February 2011

Abstract
A major challenge in the development of specific and effective targeted treatments is the paradoxical situation: one needs to exploit surface molecular targets for achieving tumor selectivity and nevertheless needs to deliver the therapeutic inside the target cell, e.g. to the cell nucleus because subcellular targeting is generally required for maximizing the therapeutic effect.
We created modular nanotransporters (MNT) unifying these 2 contradictory features into one chimeric macromolecule consisting of:- (i) an internalizable ligand module, (ii) a module with nuclear localization sequence, (iii) an endosomolytic module, and (iv) a carrier module. The modules retained their functions within the MNT: they showed high-affinity interactions with target receptors and alpha/beta-importin dimers, and form holes in lipid bilayers at endosomal pH. Anti-cancer therapeutics (photosensitizers, alpha-particle emitting radionuclides) carried by MNT acquired 20-3000 times greater cytotoxicity and cell specificity if compared with free therapeutics.
Herein, we have demonstrated in vivo that MNT possess a unique combination of properties compared with other scaffolds for drug delivery such as antibodies, nanoparticles, and liposomes. The MNT can be freeze-dried and reconstituted without loss of activity. Different modules can be inserted into the MNT in order to impart them with a specific set of capabilities; the modules are interchangeable, so they can be adapted for different cell types and/or different subcellular targets. The MNT can be used for the delivery of many types of therapeutics; they demonstrate low toxicity and low induction of delayed type hypersensitivity in mice. The MNT accumulated in murine tumors with high tumor: non-tumor ratios and displayed preferential accumulation in the subcellular compartment of choice, e.g. the cell nucleus. And finally, anti-cancer therapeutics carried by MNT acquired significantly greater cytotoxicity and cell specificity compared with free therapeutics.
We think that the MNT represent a new platform for targeted drug delivery that could be applied to the treatment of aberrant cell populations characterized by up regulation of a receptor for which there is a known ligand.
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 5485.
Abstract 5487: A new generation of tumor targetable polymeric nanoparticles for cancer therapy and imaging
Authors: Kim Jong-Ho , Bae Sang Mun , Kim Kwangmeyung , Lee Byung-Heon , Park Rang-Woon , Kwon Ick Chan , Kim In-San 
Published: February 2011

Abstract
Despite the significant progress in the development of anticancer technology, there is still no common cure for patients with malignant diseases. Conventional anticancer treatments are nonspecific to target killing of tumor cells, and always lead to systemic toxicity, causing undesirable severe side effects such as hair loss, damages to liver, kidney, and bone marrow. In order to achieve therapeutic levels of drug at the tumor site without damaging healthy organs and tissues, it is important to recognize the physiological differences between diseased and normal sites. Targeting drug delivery system is attracting increasing interest in research field to remove severe side effects and to increase reorganization of physiological differences. Polymeric nanoparticles can accumulate and extravasate within tumor tissue since their prolonged circulation by enhanced permeation and retention (EPR) effect, passive targeting system, which is achieved due to disorganized vascularization and defective vascular architecture induced in rapidly growing cancers. Even though passive targeting system shows moderate tumor therapeutic efficacy, active targeting drug delivery system has recently gained considerable attention to improve specificity. Especially, ligand/receptor-medicated targeting has emerged as a novel paradigm in the active targeting. Here, we have investigated active targeted polymeric nanoparticles by conjugation of tumor-specific homing peptide, AP-1 peptide, with modified glycol chitosan nanoparticles. Selection of peptides which show preferential binding to the target can be achieved by biopanning phage-displayed peptide libraries. Phage display technique is a promising tool for selecting peptides or proteins with specific binding properties from a lot of variants. AP-1 peptide can bind with interleukin-4 receptor which expressed on surface of several human cancer cells like H226 and MDA-MB231. Developed peptide-guided targetable polymeric nanoparticles show more specific binding and uptake as well as better therapeutic efficacy than net polymeric nanoparticles, passive targeted nanoparticles, which were confirmed with flowcytometry, immunofluorescence, histology, immunohitochemistry studies and animal experiments. In addition, they are better candidate as an imaging probe for cancer imaging and diagnosis than net polymeric nanoparticles. In conclusion, AP-1 peptide-conjugated chitosan nanoparticles are effective candidate as drug carrier and imaging probe for cancer therapy and imaging since AP-1 peptide induces the improvement of cell binding and uptake of nanoparticles.
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 5487.
Abstract 5488: Merging structure-activity relationship and nanotechnology to re-engineer cisplatin
Authors: Paraskar Abhimanyu S. , Soni Shivani , Chaudhuri Padmaparna , Sengupta Shiladitya 
Published: February 2011

Abstract
The use of nanovectors holds the potential to revolutionize cancer chemotherapy by specifically targeting tumor. A number of polymeric nanovectors are currently in development or in clinics, and are dramatically altering the pharmacodynamics and pharmacokinetics profile of the active agent. However, most of these polymeric constructs decrease the potency of the conjugated active agent, relying on increased uptake into the tumor for the improved therapeutic index. Furthermore, the nanovector formulation of small molecules such as cisplatin, which is a first-line therapy for multiple cancers, has been a challenge. So there is an urgent need to design a nanoparticle which will release a drug at its target site without decreasing efficacy of cisplatin. In the present study, we synthesized cisplatin-poly-isobutylene-maleic acid modified with glucosamine conjugate, which self assembles into nanoparticles with unique size depending on cisplatin to polymer ratio. The poly-isobutylene-maleic acid modification with glucosamine, mimicking glycans, not only increases hydrophilicity but also gives unique structural facilitation to polymer backbone so it can hold cisplatin by caboxylato and coordinate bond. The release kinetics of these nanoparticles reveals that the cisplatin release is pH dependent, and is released faster in lower pH than neutral or basic condition. We found that the these nanoparticles were taken up by cancer cells within 6 hours and inhibited proliferation and induced apoptosis in lung and breast cancer cells in vitro. In an in vivo lung and breast cancer models, the nanoparticles reduce tumor growth significantly with reduced systemic toxicity as compared to free cisplatin. In conclusion we have demonstrated that rationally re-engineered cisplatin nanoparticles improved therapeutic index for lung, breast and transgenic ovarian murine cancer models, which can be harnessed in the clinical management of 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 5488.
Abstract 5489: The IVECT™ method, a versatile micelle for the delivery of chemotherapeutic drugs
Authors: Rios-Doria Jonathan , Carie Adam , Cardoen Gregoire , Sill Kevin 
Published: February 2011

Abstract
The development of new therapeutic agents has dramatically improved the quality of life and survival rate of patients suffering from a variety of disorders. However, drug delivery innovations are required to further improve the success rate of these treatments because approximately 40% of the newly discovered, promising small molecule therapeutics have poor aqueous solubility and cannot be delivered systemically. Rationally-designed, nanoscopic drug carriers offer a promising approach to achieving these goals due to their inherent ability to overcome multiple biological barriers. Ideally, a drug delivery system will not only be stable to systemic administration, but also be versatile enough to encapsulate a diverse range of molecules leading to decreased developmental and regulatory hurdles. These goals were the driving force behind the development of Intezyne's IVECT™ Method, which is based on tri-block copolymer micelle technology; spherical nano-sized drug carriers formed by the assembly of amphiphilic block copolymers in water. This modular drug delivery platform can be tailored to accommodate a wide range of drugs, biologics or diagnostics, improve post-administration stability, vary the micelle size, control the release of the therapeutic, and target specific diseased cells based on active targeting strategies. The purpose of this study is to demonstrate encapsulation of a variety of chemotherapeutics utilizing one polymer system, and show that crosslinked micelles have improved pharmacokinetic and toxicology profiles compared to the free drugs in animal models. To this end, formulations of gemcitabine, paclitaxel, doxorubicin and SN-38 were prepared and characterized for nanoparticle size distribution by DLS and active drug weight loading by HPLC. All micelles were 30-80 nm in size with weight loadings of between 2 and 10 %. PK data from cannulated rats demonstrated significant improvement in the CMax and AUC for encapsulated crosslinked formulations, compared to the free drugs. Toxicity profiling in CD-1 mice demonstrated that the polymer alone was very safe, as an MTD was not reachable, and that the crosslinked encapsulated formulations were tolerated at significantly higher doses compared to the free drugs. In conclusion, we have demonstrated that Intezyne's IVECT™ Method is extremely versatile and results in significant improvements in the overall pharmacology of chemotherapeutics.
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 5489.
Abstract 5498: Prognostic tools to predict the efficacy of anticancer drug treatment targeting Chromatin DNA or enzymes acting on DNA
Authors: Nalabothula Narasimharao , Ross Douglas D. , Carrier France 
Published: February 2011

Abstract
There is currently no prognostic tool that can predict or monitor a cancer patient's response to anticancer drugs targeting chromatin DNA or enzymes acting on DNA. Cancer patients generally receive chemotherapy without the possibility to determine a priori whether the proposed regimen will be effective. We have developed a simple quantitative assay to measure the efficiency of Topoisomerase 2 (Topo2) inhibitors on genomic DNA (gDNA). The technique combines PCR-stop assay to real time PCR (RT-PCR). Prior reports have demonstrated that Topo2 poisons such as VP16 (etoposide) and Doxorubicin, induce prominent DNA cleavage in the P2 promoter of the c-myc gene. Therefore, we have optimized the design of primers complimentary to the sequence of Topo2 sites in the c-myc locus to suit the sensitivity of real time PCR detection. In PCR-Stop assay, the extent of locus-specific DNA damage sustained by the cells is inversely proportional to the levels of DNA amplification. The PCR-stop-RT-PCR assay was first carried out on gDNA isolated from normal and cancer cells that were either untreated or treated with a combination of Histone Deacetylase and Topo2 inhibitors. Our data indicate that the levels of DNA damage correlate with the levels of histone H2AX phosphorylation and are proportional to the efficiency of the drug combination as measured by survival assays. The potential clinical application of the assay was tested on PBMC of two leukemia patients treated with oral VorinostatSAHA (400 mg/day for three days). Our data indicate that Vorinostat increased the sensitivity of both patients PBMC to VP-16 by about 40%. One main advantage of this technique is that it uses small amounts of sample DNA (50-100 ng) to assess the efficiency of a particular drug or drug regimen. This assay could be used as a diagnostic tool for pre-clinical or clinical assessment of drug efficiency, evaluation of regimen suitability for a given patient and determination of optimal drug doses.
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 5498.