bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4405: Orthogonal detection of thymidine analogue based cell proliferation and apoptosis using click chemistry combined with antibody based progesterone receptor detection in estradiol treated rat model
Authors: Clarke Scott T. , Arumugam Arunkumar , Lakshmanaswamy Rajkumar 
Published: February 2011

Abstract
Detection reagents which can simultaneously measure cell proliferation and apoptosis, or measure chronological changes in cell proliferation over the course of a treatment provide insight into efficacy and mechanisms of treatment on cell cycle and cell heath. Detection reagents which can temporally separate cell proliferation while combined with apoptosis detection provide a powerful new investigative tool. When 5-ethynyl-2′-deoxyuridine (EdU) incorporation is used in conjunction with bromodeoxyuridine (BrdU), cell proliferation measurements are made with orthogonal detection platforms permitting unambiguous identification of proliferation events. In rat mammary epithelial tissue changes in cell proliferation as a result of treatment combined with apoptosis detection demonstrates the value of click chemistry when combined with antibody based detection methods.
We use the rat model to show changes in proliferation and apoptosis rates in mammary epithelial tissue, after alteration in hormone treatment. Use of click chemistry labeling in ovariectomized rats shows a decrease in proliferation rate from their basal levels, while estradiol treatment results in an increase in proliferation rate over basal level. Cessation of a 7 day estradiol treatment causes a drop in proliferation rate and an increase in apoptosis which can be efficiently detected using click chemistry. Progesterone receptor levels are measured simultaneously with proliferation rate when click chemistry based detection is combined with antibody based detection methods.
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 4405.
Abstract 4411: Novel internalizing human scFvs targeting pancreatic tumor cells residing in their natural tissue microenvironment
Authors: Zhu Xiaodong , He Jiang , Zhang Xiaoju , Liu Yue , Zheng Guixi , Feng Jinjin , Su Yang , Kim Grace , Tempero Margaret , Liu Bin 
Published: February 2011

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States with a five-year survival rate of about 4%. Current diagnostic and therapeutic regimens are limited and ineffective. The goal of this project is to develop novel internalizing human antibodies that target pancreatic tumor cells residing within their natural tissue microenvironment, and possess the ability to translocate through the cell membrane to reach the inside of live tumor cells. Antibodies with these two properties, i.e., being able to target tumor cells in human tissue specimen and to penetrate live tumor cells, can in the future be used to develop minimally invasive imaging strategy for earlier detection and targeted therapy that requires efficient and specific accumulation of payloads inside tumor cells. To achieve this objective, we have selected a large naïve phage antibody display library that we have recently constructed on microdissected human PDAC tissue specimens. We have identified a panel of internalizing human single chain antibodies (scFvs) that target pancreatic tumor cells in situ residing in their natural tissue microenvironment. Immunohistochemistry analysis showed that these scFvs bound to human PDAC, thereby recognizing clinically represented tumor antigens as opposed to cell line artifacts. All antibodies studied are internalized by PDAC cells in vitro. Using single photon emission computed tomography / computed tomography (SPECT/CT), we showed that technetium-labeled scFvs target human xenograft PDAC cells in vivo. Interestingly, a subset of these scFvs also target murine pancreatic tumor cell lines derived from transgenic PDAC mice, indicating that they target tumor epitopes conserved between human and mouse. Antibodies targeting tumor antigens across species would allow future imaging and therapy studies to be performed not only in xenograft but also transgenic PDAC models.
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 4411.
Abstract 4414: EC0531: A potent folate-targeted tubulysin conjugate
Authors: Leamon Christopher P. , Reddy Joseph A. , Wang Yu , Dorton Ryan , Westrick Elaine , Bloomfield Alicia , Vetzel Marilynn , Klein Patrick J. , Vlahov Iontcho R. 
Published: February 2011

Abstract
Our lab is focused on the discovery and development of highly potent chemotherapeutic agents that target folate receptor (FR) expressing malignancies. One such compound, EC0305, represents a folate-tubulysin B construct capable of specifically eradicating well-established, FR-positive subcutaneous tumors from mice [Cancer Res (2008) 68:9839]. Recently, multiple polar carbohydrate segments (e.g. 1-amino-1-deoxy-glucitolyl–glutamate) were placed in-between the folate and tubulysin B moieties (i.e. the spacer region) of EC0305 to create a new compound with more desirable biological properties. When tested in culture, this novel agent, herein referred to as EC0531, was found to specifically inhibit the growth of FR-positive cells (IC50 of ∼ 2 nM) in a dose-dependent manner. Its cytotoxic activity was blocked in the presence of an excess of folic acid, and no activity was observed against FR-negative cells, thereby demonstrating this compound's target specificity. EC0531′s potency was confirmed againstin a human KB xenograft-nu/nu mice cancer model. Here, EC0531 therapy displayed remarkable anti-tumor activity (5/5 cures) with dose levels that did not cause weight loss or major organ tissue degeneration. In contrast, the anti-tumor activity was completely abolished (0/5 remissions) in EC0531-treated animals that were co-dosed with a benign folate-containing analog. The advantage provided by folate conjugation was further proven by the un-targeted free drug, which was found to be completely inactive (0/5 remissions) at both tolerable and highly toxic dose levels. Collectively, these results show that this potent anti-proliferative tubulysin compound can be specifically delivered to FR-positive tumors to provide substantial therapeutic benefit using well tolerated dosing regimens.
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 4414.
Abstract 4418: ENMD-1198, a new microtubule-targeting agent with potent anti-vascular properties
Authors: Pasquier Eddy , Sinnappan Snega , Munoz Marcia , Kavallaris Maria 
Published: February 2011

Abstract
The formation of a new vascular network, by a process called angiogenesis, is a key driver in tumor growth and metastasis, making this an attractive therapeutic target in the fight against cancer. Different strategies are being developed to either prevent tumor angiogenesis (anti-angiogenic therapy) or disrupt the tumor vasculature already in place (vascular-disrupting therapy). ENMD-1198 is a new analogue of 2-methoxyestradiol (2-ME2), a microtubule-targeting agent that has shown promising results in the treatment of multiple myeloma, hormone refractory prostate cancer and recurrent ovarian cancer. Pre-clinical in vivo studies have shown that ENMD-1198 displayed improved metabolic stability as compared to its parental compound (2-ME2) and retained potent anti-tumor activity [1, 2]. We hypothesized that ENMD-1198 may also exhibit improved anti-angiogenic and/or vascular-disrupting properties. Using both bone-marrow derived and dermal microvascular endothelial cell lines, we thus analyzed and compared the effects of ENMD-1198 and 2-ME2 on the different functions of endothelial cells involved in angiogenesis. In both cell lines, ENMD-1198 was more potent than 2-ME2 at inhibiting endothelial cell proliferation, motility, migration and morphogenesis. In addition, videomicroscopy experiments revealed that ENMD-1198 was able to completely disrupt pre-formed vascular structures within 2 hours. This vascular-disrupting activity was associated with extensive depolymerisation of microtubules, accumulation of actin stress fibers and alteration in focal adhesions. Collectively, our results demonstrate that this new compound displays improved anti-vascular properties and this study provides important insights into the mechanism of action of ENMD-1198, a promising new anti-cancer drug.
1. LaVallee T.M, Burke P.A, Swartz G.M et al. (2008) Mol Cancer Ther.7: 1472-82.
2. Moser C., Lang S.A., Mori A. et al. (2008) BMC Cancer 8:206.
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 4418.
Abstract 4426: Are there synergistic antiproliferative effects of paclitaxel and curcumin on osseus metastasis of renal cell carcinoma
Authors: Reinecke Petra , Biewer Matthias , Kalinski Thomas , Gabbert Helmut Erich 
Published: February 2011

Abstract
Aim: Human renal cell carcinomas (RCCs) are highly resistant to conventional chemotherapy. Recently, paclitaxel has been shown to inhibit growth of RCCs in vitro. Therefore, we analyzed the chemotherapeutic potential of paclitaxel on our established cell line N109, derived from an osseous metastasis of a human RCC. In addition, we examined the role of the phytochemical curcumin on the growth inhibition which is known to act as a modulator of the Multidrug Resistance Phenotype. Methods: MTT assay, immunfluorescence microscopy and flow cytometry. Results: 1. Significant dose-dependent growth inhibition and paclitaxel-induced morphological alterations were observed in the cell line N109. 2. No significant dose-dependent growth inhibition was observed after exposure to curcumin alone. 3. A synergistic effect of growth inhibition was detected after treatment with both, paclitaxel and curcumin. 4. The cell line N109 shows a pronounced P-glycoprotein expression. 5. After exposure to paclitaxel or curcumin no remarkable modulation of the P-glycoprotein expression level was observed. Conclusion: This study demonstrates that paclitaxel can effectively inhibit the growth of an osseous metastasis of human renal cell carcinoma in vitro whereas a pronouced synergistic inhibition effect in combination with the phytochemical curcumin became evident.
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 4426.
Abstract 4428: A novel imidazo[4,5-b]pyridine Aurora kinase inhibitor with anti-leukemic activity
Authors: Moore Andrew , Bavetsias Vassilios , Sun Chongbo , Faisal Amir , Workman Paul , Blagg Julian , Pearson Andrew , Linardopoulos Spiros 
Published: February 2011

Abstract
The Aurora kinases are a family of highly conserved serine-threonine kinases that play key roles in several stages of mitosis. Over-expression of these kinases has been demonstrated in a range of malignancies including leukemia. Aurora kinase inhibitors are emerging as promising agents in the treatment of acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). The activity of this class of drugs in AML and CML may be in part due to their ability to also inhibit the tyrosine kinases FLT3 and Abl1 respectively. Here we report the activity of a novel imidazo[4,5-b]pyridine derivative developed at our institution with potent inhibition of Aurora A and B kinases (IC50 values of 6 nM and 45 nM respectively). Furthermore, the IC50 for FLT3 kinase is &lt; 0.5 nM, whilst the IC50 for Abl1 kinase is 82 nM. Consistent with the potent kinase inhibition profile, the AML cell lines MV-4-11 and MOLM-13 are particularly sensitive with GI50 values less than 50 nM. Cellular assays demonstrate that this imidazo[4,5-b]pyridine derivative inhibits phosphorylation of histone H3, a direct target of Aurora B kinase, as well as phosphorylation of FLT3 and the downstream p44/42 MAP kinases in these cell lines. Both MV-4-11 and MOLM-13 carry internal tandem duplications of the FLT3 receptor tyrosine kinase (FLT3-ITD), which is clinically associated with a poor prognosis in AML. The potent preclinical activity in FLT3-ITD positive cell lines supports the growing body of evidence that dual pan-Aurora and FLT3 kinase inhibitors may be of benefit in the high-risk group of patients with FLT3-ITD positive AML.
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 4428.
Abstract 4429: Characterization of the kinesin spindle protein inhibitor AZD4877
Authors: Pinzon-Ortiz Maria C. , Cao Alex , Sheehy Adam , Pablo Lourdes , McEachern Kristen , Hylander-Gans Linda , Wu Kaida , Reimer Corinne , Morosini Deborah , McCoon Patricia , Huszar Dennis 
Published: February 2011

Abstract
The process of mitosis is a validated point of intervention in cancer therapy and a variety of anti-mitotic drugs are successfully being used in the clinic. To date, all approved antimitotics target the spindle microtubules, thus interfering with spindle dynamics, leading to mitotic arrest and apoptosis. While effective, these drugs are also associated with a variety of side effects, including neurotoxicity. In recent years, mitotic kinesins have attracted significant attention in the search for novel, alternative mitotic drug targets. In addition, kinesin inhibitors may overcome resistance to microtubule targeting drugs.
Here we describe the pharmacological evaluation of AZD4877, a selective Eg5 inhibitor. AZD4877 exhibits potent cell growth inhibition in vitro against a broad panel of both solid and hematological tumor cell lines. Efficacy is associated with formation of monoastral spindles, mitotic block and the induction of apoptosis. AZD4877 also demonstrates activity in multiple tumor xenograft models, including primary bladder tumor explants and a Rituximab-insensitive non-Hodgkin's Lymphoma model (DoHH2T53). Combination studies with a taxane agent (Docetaxel) demonstrate additive efficacy of tumor growth inhibition, with notable tumor regrowth delay in the combination arm. In summary, AZD4877 is an active Eg5 inhibitor with potent anti-tumor activities in vitro and in vivo. The efficacy observed in combination studies and in a rituximab-resistant tumor model suggests possible clinical applications for this agent.
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 4429.
Abstract 443: Effects of ACNU on U87 monolayer cultures and spheroids are dependent on hypoxia
Authors: Kolenda Jesper , Aaberg-Jessen Charlotte , Jensen Stine Skov , Kristensen Bjarne Winther 
Published: February 2011

Abstract
Tumor hypoxia and the presence of tumor stem cells are features related to glioblastoma tumorigenicity and malignancy. Moreover, chemotherapy seems to have limited effects on tumor stem cells. In the present study the aim was to investigate this further using U87 monolayer cultures, but also the more in vivo like multicellular spheroids. We investigated the effect of nimustine (ACNU) on U87 monolayer cultures and spheroids cultured in 1 % and 21 % oxygen. A WST-1-based cytotoxicity assay and a clonogenic assay were used for detection of effects of ACNU on monolayer cultures. Moreover, spheroids were exposed to ACNU and the effect evaluated by a clonogenic assay and immunohistochemical staining on spheroid paraffin sections using markers of apoptosis (caspase-3, TUNEL), stem cell related markers (CD133, podoplanin, Bmi-1, nestin) and the proliferation marker (Ki-67). We found hypoxia to reduce the effect of ACNU on U87 monolayer cultures and spheroids in both WST-1 and clonogenic assays. In spheroids, this was confirmed by caspase-3 and TUNEL staining. Furthermore, stem cell markers were preserved to a higher extent in hypoxia. However, this preservation was not seen with the proliferation marker Ki-67. In conclusion, the present study underlines the role of tumor hypoxia in chemoresistance, suggesting that the more immature features related to tumor stem cells may contribute to this.
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 443.
Abstract 4447: Targeting Hsp90 with small molecule inhibitors induces the overexpression of the anti-apoptotic molecule, survivin, in human cancer cells
Authors: Cheung Chun Hei Antonio , Chen Huang-Hui , Cheng Li-Ting , Lyu Kevin W. , Kanwar Jagat R. , Chang Jang-Yang 
Published: February 2011

Abstract
Survivin is a dual functioning protein. It inhibits the apoptosis of cells by inhibiting caspases, and also promotes cell growth by stabilizing microtubules during mitosis. Furthermore, over-expression of survivin has been shown to induce drug resistance to various chemotherapeutic compounds. Since the molecular chaperone Hsp90 binds and stabilizes survivin, it is widely believed that down-regulation of survivin is one of the important therapeutic functions of Hsp90 inhibitors such as the phase III clinically trialed compound 17-AAG. However, Hsp90 interferes with a number of molecules that positively regulate the intracellular level of survivin, raising the question that clinical use of Hsp90 inhibitors may indirectly induce survivin expression and subsequently promote cancer progression under certain circumstances. Here, we demonstrated that Hsp90 inhibitors, geldanamycin and 17-AAG, induced the over-expression of survivin in three different human cancer cell lines as shown by western blotting. Increased survivin mRNA transcripts were observed in 17-AAG and geldanamycin-treated HT-29 and HONE-1 cancer cells. Interestingly, real-time PCR and translation inhibition studies revealed that survivin was over-expressed partially through the up-regulation of protein translation instead of gene transcription in A549 cancer cells. In addition, 17-AAG-treated A549, HONE-1 and HT-29 cells showed reduced amount of 26S proteasome and decreased proteasomal activity while inhibition of 26S proteasome further increased the amount of survivin protein in cells. At the functional level, down-regulation of survivin by siRNA further increased the drug sensitivity to 17-AAG in the tested cancer cell lines. In conclusion, we showed for the first time that targeting Hsp90 induced the over-expression of survivin through various mechanisms in cancer cells. These data indicate that down-regulation of survivin is not a definite therapeutic function of Hsp90 inhibitors. The current study suggests that dual inhibition of Hsp90 and survivin may be warranted.
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 4447.
Abstract 4454: Modulation of the early cytotoxic effects of Irvalec® by zinc and DIDS in lung tumor cells
Authors: Molina-Guijarro José M. , Moneo Victoria , Martínez-Leal Juan F. , Cuevas Carmen , Garcia-Fernandez Luis F. , Galmarini Carlos M. 
Published: February 2011

Abstract
Irvalec®, a marine-derived depsipeptide, has showed potent cytotoxic activity in vitro against a wide variety of human tumors, including breast, colon, pancreas, lung and prostate. Irvalec® is currently undergoing phase II clinical studies in non-small lung cancer. Exposure of tumor cells to Irvalec® induces necrotic cell death, a process associated with rapid loss of membrane integrity and subsequent cell permeabilization. In dose-response experiments using different tumor cell lines, very similar IC50 values were obtained after short (30 min) and long (72 h) exposure times to the drug, suggesting that the compound exerts its cytotoxic effect immediately after drug treatment. Tumor cells exposed to effective concentrations of Irvalec® underwent rapid and dramatic morphological changes, including cell blebbing, severe swelling, and plasma membrane permeabilization (as detected by propidium iodide (PI) uptake and LDH release) that irrevocably lead to cell lysis. Interestingly, membrane damage was observed only after reaching a threshold concentration of around 1-5 µM and only in the continuous presence of the compound in the culture medium. Compounds acting at the cell membrane have been reported to have similar cellular effects than those observed with Irvalec®. The activity of these compounds was inhibited by the use of different cell membrane protectors. To test if these protectors exert some effect against the cytotoxic activity of Irvalec® we exposed A549 cells to a panel of 20 different compounds and then treated with Irvalec®. The cytotoxic activity of the drug was evaluated by PI nuclear staining by fluorescence microscopy, time-lapse videomicroscopy and plate fluorimetry. Among the compounds tested, only DIDS (dihydro-4,4′ diisothiocyanostilbene-2,2′-disulphonic acid) and zinc salts resulted in a drastic reduction of the early effects of Irvalec® in A549 cells. In the presence of DIDS or zinc, a 70% and 90% decrease was observed, respectively, in the cytotoxicity of the drug. Altogether, these results suggest that Irvalec® induces a rapid hydroelectrolitic disbalance in tumor cells, causing severe alterations that lead to a necrotic cell death.
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 4454.