bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A137: Chemotherapy molecule delivered by tumor-targeted salmonella enterica serovar typhimurium under the control of integrated modular gate
Authors: Yumei Dai , Forbes Neil S. 
Published: June 2012

Abstract
Several strictly or facultative anaerobic bacteria have attracted more and more attention in cancer therapeutics because of their targeting and accumulating abilities in solid tumors, and Salmonella enterica serovar Typhimurium is one of them. These bacteria were also adapted to deliver therapeutic factors and were applied alone or in combination with conventional therapeutics. The aim of this study is to test a new integrated gene expression system in S. Typhimurim SL1344, and the benefit of the new system in amplifying therapeutic molecule production during bacterium targeting and accumulating in solid tumor. We have constructed a synthetic genetic gate in S. Typhimurim SL1344 that integrates information from two promoters as inputs and actives a promoter output only when both input promoters are induced. The integration occurs via an interaction between L-arabinose concentration and bacterium cell density. When certain amount of L-arabinose were added in the system and bacterium population were higher enough, the tumor necrosis factor apoptosis inducing ligand(TRAIL) and fluorescent protein ZsGreen as the control were produced by bacteria. LS174T colon carcinoma cells were processed to form cylindroids between the bottom surface of a 96-well plate and the top surface of a set of polycarbonate cylindrical plugs attached to a polycarbonate lid to mimic solid tumor, and then cylindroid cultures were inoculated with S. typhimurium SL1344 carrying TRAIL or ZsGreen expression system. 0.2% (w/v) L-arabinose was added into the well after 12hr inoculation, and then washed out after 2hr induced. Extents of apoptosis in cylindroids were tested by caspase-3 activity assay. Results showed that the bacteria accumulated inside cylindroids indicated by ZsGreen expression, and the average normalized intensity of apoptotic cell was higher in the cylindroids inoculated by the bacteria carrying the TRAIL than those inoculated by the bacteria carrying the ZsGreen. It can be concluded that the constructed integrated modular gate could effectively control bacteria to produce functional chemotherapy molecule in solid tumor at desirable time and places.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A137.
Abstract A138: Development of potent inhibitors of the DNA-dependent protein kinase (DNA-PK)
Authors: Cano Celine , Curtin Nicola , Hardcastle Ian , Golding Bernard , Smith Graeme , Newell Herbie , Griffin Roger 
Published: June 2012

Abstract
The cellular response to DNA double-strand break (DSB) formation is an essential component of normal cell survival, following exposure to DNA-damaging chemicals and ionising radiation. The serine/threonine kinase DNA-dependent protein kinase (DNA-PK) is a member of the phosphatidylinositol (PI) 3-kinase related kinase (PIKK) family of enzymes, and plays an important role in DNA DSB repair via the non-homologous end-joining (NHEJ) pathway. DNA-PK inhibitors may, therefore, be useful as agents to improve the activity of radio- and chemo-therapy in the treatment of cancer.
Identification of the lead benzo[h]chromen-4-one DNA-PK inhibitor NU7026 (IC50 = 0.23 uM) guided the development of the potent and selective ATP-competitive chromenone NU7441 (DNA-PK IC50 = 30 nM). Structure-activity relationship studies for DNA-PK inhibition by chromenone-derivatives were conducted in conjunction with homology modelling. Library synthesis was undertaken employing a solution multiple-parallel approach, by O-alkylation or N-acylation of the appropriately substituted NU7441 derivatives, respectively, followed by reaction with a range of amines to afford the target compounds. These studies resulted in the identification of KU-0060648, which combines high potency as a DNA-PK inhibitor (IC50 = 8.6 nM) with good aqueous solubility as an acid salt. The further development of KU-0060648 and analogues will be described.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A138.
Abstract A14: sFLT01: An antiangiogenic protein that neutralizes placental growth factor
Authors: Bagley Rebecca G. , Kurtzberg Leslie , Weber William , Nguyen Tri-Hung , Lovewell Gwen , Nguyen Cokey , Yao Min , Roth Stephanie , Krumbholz Roy , Crawford Jennifer , Pechan Peter , Shankara Srinivas , Scaria Abraham , Schmid Steve , Brondyk Bill , Kaplan Johanne , Teicher Beverly A. 
Published: June 2012

Abstract
Introduction: Anti-angiogenic agents have shown clinical value in combination with chemotherapy by targeting the VEGF pathways. The development of tumor vasculature in human renal cell carcinomas (RCC) is stimulated not only by VEGF but by other angiogenic growth factors such as placental growth factor (PlGF) [1,2]. In the current study, we used a novel fusion protein, sFLT01, that includes human VEGFR1 domain 2 and an IgG1 Fc, which binds to both human VEGF and PlGF. The anti-angiogenic activity of sFLT01 was evaluated in several preclinical models of RCC.
Methods: The binding affinity of sFLT01 for PlGF was evaluated in vitro in binding assays quantified by ELISA and Octet and in proliferation assays where endothelial cells are stimulated by PlGF. The ability of sFLT01 to slow tumor growth was evaluated in the 786-O human RCC xenograft model as well as in the mouse RENCA RCC orthotopic and subcutaneous tumor models. sFLT01 was delivered by intraperitoneal injection twice per week at doses ranging from 5–25 mg/kg. Microvessel density (MVD) and other vascular parameters were analyzed in the syngeneic and xenograft tumors by immunohistochemical methods with an antibody against mouse CD31 to identify endothelial cells.
Results: sFLT01 bound to human PlGF with great affinity and inhibited HUVEC proliferation with an IC90 of approximately 2.3 nM. Subcutaneous 786-O RCC tumors were inhibited at a dose of 25 mg/kg and median survival time was increased by 33% in the orthotopic RENCA model. sFLT01 reduced MVD in subcutaneous RENCA tumors by approximately 50% and lumen area by approximately 66%. In the 786-O xenograft model, 5 or 25 mg/kg sFLT01 reduced the blood vessel area, lumen size, and vessel perimeter compared to control.
Conclusions: sFLT01 is effective at inhibiting blood vessel growth in tumors by binding VEGF and PlGF thereby preventing the development of new vasculature and decreasing existing vasculature. sFLT01 reduces intratumoral blood vessel count, prolongs survival, and delays tumor progression in the RENCA and 786-O renal cell carcinoma models. As an anti-angiogenic agent, sFLT01 may be useful in treating human renal cell carcinomas.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A14.
Abstract A140: Identification of substituted isoindolinones as potent inhibitors of the MDM2-p53 protein-protein interaction
Authors: Watson Anna , Liu Junfeng , Armstrong Elizabeth , Blackburn Timothy , Endicott Jane A. , Golding Bernard T. , Griffin Roger J. , Lu Xiaohong , Newell David R. , Noble Martin E.M. , Riedinger Christiane , Lunec John , Hardcastle Ian R. 
Published: June 2012

Abstract
The p53 tumor suppressor plays a pivotal role in the cell by reacting to stress, which may be caused by hypoxia, DNA damage, or oncogenic signalling. Activation of p53 protein results in the transcription of a number of genes that govern progression through the cell cycle, the initiation of DNA repair, and apoptosis. The activity of p53 is tightly regulated by the MDM2 protein, which is transcribed in response to p53 activation. MDM2 binds to and inactivates p53 and also ubiquitylates the MDM2-p53 complex to target it for proteosomal degradation. In normal cells the balance between active p53 and inactive MDM2-bound p53 is maintained in a negative feedback loop.
Inhibition of the MDM2-p53 protein-protein complex by small molecule inhibitors is expected to reactivate normal p53 pathways in cells overexpressing MDM2, consequently exerting an anti-cancer effect. Potent small molecule inhibitors of the MDM2-p53 interaction have been identified e.g. the Nutlins [Science 2004, 303, 844], the benzodiazepinediones and indolinones [J. Med. Chem. 2006, 49, 3759–3762]. The antitumor activities of these compounds in cellular and in vivo models are promising.
We have reported previously inhibitors of the MDM2-p53 interaction, based on an isoindolinone scaffold [J. Med. Chem. 2006, 49, 6209–6221], and SAR studies leading to compounds with improved potency e.g. NU8345A; IC50 = 171 ± 15 nM. NMR structural studies suggested that substitution of the isoindolinone A-ring may provide additional favourable interactions with the protein. A small series of examples was prepared, and 4-substitution with small hydrophobic groups was found to improve potency e.g. rac-4-methyl-3-(4-chlorophenyl)-3-((1-(hydroxymethyl) cyclopropyl)methoxy)-2-(4-nitrobenzyl)isoindolin-1-one (NU8405; IC50 = 274 ± 35 nM) and rac-4-chloro-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(4-nitrobenzyl)isoindolin-1-one (NU8406; IC50 = 143 ± 26 nM). Introduction of a 6-tert-butyl group was also found to be favourable i.e. rac-6-tert-butyl-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(4-nitrobenzyl)isoindolin-1-one (NU8399; IC50 = 152 ± 27 nM). Resolution of the enantiomers of NU8406, using chiral HPLC, gave NU8406A and NU8406B (IC50s of 43.8 ± 6.2 nM and 1.27 ± 0.08 M, respectively).
The cellular activities of key compounds have been determined and show dose dependent induction of p53 regulated genes by Western blotting. NU8406 shows selective cytotoxicity in p53wt HCT116 cells compared with the HCT116−/− line (GI50s = 9.8 ± 1.1 and 21.3 ± 3.1 M, respectively) which is comparable to Nutlin-3 (ELISA IC50 = 66.2 ± 5.7 nM; GI50s = 8.9 ± 0.5 and 38.8 ± 3.4 M, respectively).
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A140.
Abstract A143: Novel temozolomide analog may overcome MGMT and MMR
Authors: Zhang Jihong , Stevens Malcolm FG , Kerschmeier Paul , Hummersone Marc , Laughton Charles A. , Bradshaw Tracey D. 
Published: June 2012

Abstract
Glioblastoma multiforme (GBM) is the most common and lethal type of brain cancer. The current standard of care for GBM patients includes surgery, radiotherapy and oral alkylating agent temozolomide (TMZ) chemotherapy. The cytotoxic activity of TMZ is dependent on DNA repair pathways, being inversely related to O6-methylguanine methyltransferase (MGMT) levels and dependent on functional mismatch repair (MMR). Intrinsic or emergent acquired resistance to TMZ presents severe obstacles to successful treatment. Therefore, TMZ analogs have been designed to overcome TMZ resistance, potentially possessing a broader spectrum of anti-cancer activity. Activities of TMZ and novel analogs were tested against 2 isogenic glioma cell line pairs: SNB19V and U373V (vector control cell lines, low MGMT) and SNB19M and U373M (MGMT overexpressing counterparts). TMZ and the corresponding triazene MTIC demonstrated 13.2- and 9.3-fold resistance in SNB19M cells; 5.4- and 4.25-fold resistance in U373M cells (compared to each vector transfected isogenic pair). Analog DC-010-116, where methoxycarbonylmethylene (CH2CO2CH3) replaces the methyl group of TMZ, and its corresponding triazene exerted growth inhibitory activity in TMZ sensitive (V) and TMZ resistant (M) cells, with GI50 values &lt; 50 µM in all 4 cell lines. In addition, MMR deficient HCT 116 colon carcinoma cells, resistant to TMZ (GI50 590.6 µM) responded to DC-010-116 treatment (GI50 44.6 µM). Therefore, DC-010-116 exerts anticancer activity irrespective of MGMT and MMR status in glioma and colon carcinoma cells. Moreover, cross-resistance to DC-010-116 was not observed in glioma cell lines with acquired TMZ resistance (SNB19VR; U373VR). DC-010-116 blocked SNB19V, SNB19M and SNB19VR cells in G2/M and caused apoptosis in a time and dose dependent manner. Cellular DNA damage was detected by Alkaline Comet Assay, and H2AX phosphorylation indicated formation of lethal DNA double strand breaks following DC-010-116 treatment. DC-010-116 showed 3.7- fold difference in activity in paired base excision repair (BER) deficient/proficient CHO cell lines; furthermore, PARP inhibition potentiated sensitivity of HCT 116 cells to DC-010-116 (3-fold). However, DC-010-116, a likely substrate for plasma esterase activity, was devoid of activity in vivo. Accordingly the hydrolyzed carboxylic acid product (CH2CO2H) was inactive in vitro. In conclusion, we demonstrate that the anticancer activity of DC-010-116 escapes MGMT and MMR, blocks glioma cells in G2/M and induces apoptosis. DNA damage, recruiting BER, was detected. However, in vivo activity was compromized by plasma esterase activity.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A143.
Abstract A151: Differential mechanisms of acquired resistance to IGF-1R antibody therapy and a small molecule inhibitor, BMS-754807 in a human rhabdomyosarcoma Rh41 model
Authors: Carboni Joan M. 
Published: June 2012

Abstract
Background: Overexpression and/or overactivation of IGF-1R have been linked to a number of cancer types including, colon, breast, prostate, lung and sarcoma. These findings support IGF-1R as a promising therapeutic target. Agents targeting IGF-1R, including IGF-1R antibodies and small molecule inhibitors are currently in clinical development. A common phenomenon resulting in clinical failures is the development of resistance to anti-cancer therapies. In the present study, the goal is to compare the mechanisms of acquired resistance to mAb391, an IGF-1R-blocking antibody and to BMS-754807, a small molecule dual inhibitor targeting IGF-1R/IR, and to provide insights on biomarkers for early detection of resistance and differentiation of IGF-1R targeted therapies.
Methods: The human Rhabdomyosarcoma cell line Rh41, which is sensitive to IGF-1R inhibition and responsive to both agents, was used to develop two acquired-resistant cell lines, Rh41-807R and Rh41-mAb391R. In addition, tumor xenograft models were developed from the resistant cell lines. Gene expression profiling was performed on the sensitive parental (Rh41), Rh41-807R, and Rh41-mAb391R cells and tumors to identify biomarkers involved in acquired resistance to BMS-754807 and/or mAb391. RNA expression profiles for selected biomarkers from both cells and tumors correlated well with protein expression patterns, as determined by Western blot analysis.
Results: Differences in resistance mechanisms between Rh41-807 and Rh41-mAb391 resistant lines were observed and each utilizes different alternative growth signaling pathways as an escape mechanism. PDGFR was found to be overexpressed at the RNA level in both Rh41-807R cells (89-fold) and tumors (27-fold) and was constitutively activated; siRNA knockdown of PDGFR in Rh41-807R re-sensitized the cells to BMS-754807. Synergistic activities were observed when BMS-754807 was combined with agents that also inhibited PDGFR in the Rh41-807R models. AXL RNA expression was found to be elevated in Rh41-mAb391R (8-fold), but down-regulated in Rh41-807R cells (5-fold). In addition, BMS-754807 was active in Rh41- mAb391R cells and able to overcome resistance to the IGF-1R antibody treated cells. However, the converse was not true i.e., mAb391 did not overcome resistance in the Rh41-807R cell line.
Conclusions: PDGFR overexpression and activation may drive resistance to BMS-754807, whereas differential resistance mechanisms are involved in resistance to the IGF-1R antibody. The activity of BMS-754807 in the Rh41- mAb391R acquired-resistant model suggests that treatment with BMS- 754807 may overcome resistance in patients who have failed treatment with IGF-1R antibodies.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A151.
Abstract A167: Simvastatin is synthetically lethal to the loss of LKB1 in lung cancer cells
Authors: Helbling Marianne M. , Schmitt Iris , Greiner Erich , Krek Wilhelm 
Published: June 2012

Abstract
‘Synthetic lethality’ offers an attractive therapeutic strategy for the development of cancer-specific cytotoxic agents. We therefore decided to exploit the genetic differences that exist between the tumor cell and the normal cell by searching for drugs that display ‘synthetic lethal’ interactions with the cancer-associated LKB1 mutation that occurs in about 30% of human lung adenocarcinomas.
Two genes are said to be ‘synthetic lethal’, if disruption of either individual gene is compatible with viability, but if loss of both causes death. It follows that a drug that is synthetic lethal to LKB1 should kill only the mutated LKB1 negative cells and spare normal cells.
A cell-based high-content screen for cell death was carried out with 48,000 small molecule compounds on an isogenic cell line pair that differs in its status of LKB1 (wild type versus mutant). We identified Simvastatin, an inhibitor of HMG-CoA reductase and widely used cholesterol-lowering drug, as one of the main hits. Other statins in the screening set, such as Lovastatin and Compactin, displayed similar activity.
Follow-up experiments confirmed synthetic lethal interactions between Simvastatin and LKB1-deficiency. Importantly, addition of mevalonate, the product of the HMG-CoA reduction rescued and siRNAs targeting HMG-CoA reductase further enhanced cell death induced by Simvastatin in LKB1-negative cells. Furthermore, Simvastatin specifically inhibited LKB1-negative tumor growth in a xenograft model in nude mice. The synthetic lethal relationship between Simvastatin and LKB1-deficiency indicates statins as potential cancer therapeutics for LKB1-negative tumors.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A167.
Abstract A171: Cytotoxicity of novel substituted purine derivatives against liver cancer cells
Authors: Guven Ebru Bilget , Tuncbilek Meral , Ersahin Tulin , Demir Zerrin , Ozturk Mehmet , Atalay Rengul Cetin 
Published: June 2012

Abstract
Cytotoxic purine and purine nucleoside analogs (PNA) are widely used in cancer treatment (1). In this study, three newly synthesized substituted purine derivatives, AUM18, AUM23 and AUM32* were evaluated for their cytotoxicities by Sulforhodamine B (SRB) assay initially on Hct116 (colon), T47D (breast), and Huh7 (liver) human carcinoma cell lines (2). The IC50 values for the cell lines analyzed were ∼2.0µM for AUM18, ∼0.5µM for AUM23 and ∼5nM for AUM32. The growth inhibitory effects that we observed with these PNAs were comparable to those of the known anticancer agents Camptothecin (IC50 ∼ 10 nM) and 5-Fluorouracil (IC50 ∼10µM). Subsequently, the cytotoxicity of each molecule was tested on the HCC cell line panel composed of Huh7, HepG2, Hep3B, Mahlavu, PLC, SkHep1, Focus, SNU-182 and SNU-475 cells. The IC50 values were again in micromolar varying between 0.1 to 10 µM range. However, we did not observe significant cytotoxic effect on SNU-182 cells with AUM18 PNA and on SNU-475 with AUM32. The differential inhibition that we observe, can be considered as an indication of the specificity of these inhibitors against their target. They might interfere with the activity of certain kinases rather than acting as a multi-kinase inhibitor. Furthermore, we evaluated the protein kinase activity inhibition potential of these novel purine analogs. Therefore, the kinase assay based on the detection of the amount of ATP in the reaction mixture through bioluminescence was performed with Huh7 and Mahlavu cells. Cells incubated with these novel kinase inhibitor candidates and Staurosporine (STS), a multi-kinase inhibitor used as positive control (4). The relative light units that we observed with novel PNAs were comparable to that of STS. Based on our observations, the newly synthesized PNAs, AUM18, AUM23 and AUM32 can be identified as protein kinase inhibitor candidates which must be further analyzed at the molecular level.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A171.
Abstract A172: Dicycloplatin in cancer
Authors: Yang Xuqing , Yu Jing Jie , Liang Xiaobing , Zhu Honglan , Mueller Michael D. 
Published: June 2012

Abstract
Dicycloplatin (DCP) is a new platinum-based drug developed in China. It possesses superior stability and water-solubility compared to cisplatin and carboplatin. Experimental findings in China demonstrate in vitro cytotoxicity of dicycloplatin against a variety of human cancer cell lines and significant in vivo antitumor activity in mouse tumor models. DCP toxicity profile of 210 mg/kg of LD50 compares favourably to 14.27 mg/kg for cisplatin and 164 mg/kg for carboplatin. Histoculture Drug Response Assay (HDRA) indicates clinical efficacy of chemotherapy for various cancer types including brain cancer. Pre-clinical and clinical studies in China suggest that DCP produces fewer side effects with a maximum tolerated dose of 650 mg/m2. In one case, DCP with radiotherapy successfully treated a lung cancer patient with brain metastasis. Polar surface area (PSA) and LogP calculations for estimating solubility and ability to cross the BBB indicate that DCP possesses the largest PSA (132) and CLogP (1), compared to carboplatin (106.2; −0.34) and cisplatin (53.6; −2.5). Investigations of molecular mechanisms at WVU suggest that DCP induces gene signature profile in human ovarian cancer cells through mechanisms similar to other platinum drugs.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A172.
Abstract A174: High-throughput screening for natural product inhibitors of human tyrosyl-DNA-phosphodiesterase (Tdp-1)
Authors: Bermingham Alun , Price Edmund , Marchand Christophe , Pommier Yves , Goncharova Katya , Evans Jason , McMahon James , O'Keefe Barry 
Published: June 2012

Abstract
Tyrosyl-DNA-phosphodiesterase I (Tdp-1) is part of the DNA repair complex that resolves irreversible topoisomerase I (Top1)-DNA cleavage complexes by catalyzing the hydrolysis of 3′-phosphotyrosyl bonds. A point mutation in the Tdp1 gene causes a neurological disorder called spinocerebellar ataxia with axonal neuropathy (SCAN1) (Takashima, 2002). SCAN1 cells display hypersensitivity to camptothecin (CPT), a potent Topoisomerase 1 inhibitor. Additionally, overexpression of a human Tdp1 fusion protein alleviates some of the effects of CPT treatment (Barthelmes, 2004). These observations suggest that inhibitors of Tdp1 could act synergistically with CPT in a combined therapeutic treatment for certain cancers.
Despite attempts to identify synthetic small molecule inhibitors of Tdp-1, there are few verified inhibitors of this enzyme activity and none currently in clinical trials. While previous screening efforts have focused mainly upon compounds of synthetic origin (Antony, 2007), little effort has been directed towards the discovery of natural product derived inhibitors. The Molecular Targets Development Program (MTDP) at NCI-Frederick has developed a fluorescence-based assay for the rapid identification and characterization of natural product derived inhibitors of Tdp1 enzyme activity. Initial high-throughput screening work has identified several unique extracts showing potent inhibition of enzyme activity. Follow up work is currently underway to evaluate the molecular mechanism of isolated active natural compounds.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A174.