bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3488: In vitro activity of the IGF-1R inhibitor CP-751,871, as a single agent and in combination with paclitaxel, in lung and colon cell lines
Authors: Agullo-Ortuño M. Teresa , Díaz-García C. Vanessa , Rodríguez Analía , Cortijo Ana , López-Martín José A. , García-Carbonero Rocío , López-Ríos Fernando , Cortés-Funes Hernán , Paz-Ares Luis 
Published: February 2011

Abstract
Background: Signaling through the insulin-like growth factor 1 receptor (IGF-1R) has been implicated in the resistance to a number of clinically relevant anti-cancer agents.
Objective: To assess the direct anti-tumour effects of the IGF-1R monoclonal antibody CP-751,871, as a single agent and in combination with paclitaxel, in lung and colon cancer cell lines.
Methods: Four lung (A549, HCC78, H1299 and H460) and four colon (LS180, Colo205, HT29 and DLD1) cancer cell lines were selected. The experiments were designed to test the effects of simultaneous or sequential exposure to with CP-751,871 and/or paclitaxel. In the sequential arm, cells were pretreated with progressive doses of paclitaxel (from 0 to1000 nM) for 24 hours, drug removed by washing the cells twice, followed by the addition of cell culture medium plus CP-751,871 (50 μg/mL). After 48 hours of continuous presence of CP-751,871, cell growth was evaluated by WST-1 cell survival assays. In simultaneous treatment, cells were treated with both Paclitaxel (0-1000 nM) and CP-751,871 (50 μg/mL) for 48 hours. Flow cytometric analysis was used to estimate the effects on cell cycle and apoptosis. IGF-IR mRNA expression was determined by quantitative real-time PCR. Relative gene expression values were calculated by the ΔΔCt method.
Results: No correlation between basal IGF-IR mRNA expression and response to CP-751,871 was observed. Flow cytometric analysis demonstrated that CP-751,871 enhanced cell cycle arrest at the G1/G0 checkpoint with minimal effects on apoptosis. Combined exposure to both CP-751,871 and Paclitaxel showed improved response in cell growth inhibition on HCC78, H1299, Colo205 and HT29 cell lines, and was statistically superior to Paclitaxel alone (p&lt; 0.001) and CP-751,871 alone (p&lt; 0.001). The results were even better after a sequential exposure. On the contrary, in H460, LS180 and DLD-1 cell lines, concomitant, but no sequential treatment resulted in antagonistic interactions. Conclusions: CP-751,871 showed a modest anti-tumour activity (about 30% growth inhibition in lung cancer cells; 10% growth inhibition in DLD1 and HT29 cell lines; and bigger inhibition in Colo205 (IC50=27.6 μg/mL) and LS180 (IC50=2.33 μg/mL) cell lines), predominantly cytostatic, that is not related to the mRNA expression. The effects of CP-751,871 in combination with paclitaxel depend on the cell line model and on the sequence of administration.
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 3488.
Abstract 3492: A novel PI3K/mTOR dual inhibitor provides correlations of pharmacokinetic pharmacodynamic and tumor growth inhibition in a prostate PC3 xenograft model for application in clinical trials
Authors: Carley William W. , Bagrodia Shubha , Yuan Jing , Ye Jingjing , Cheng Hengmiao , Sun Shaoxian , Cullnane Carleen , McArthur Grant 
Published: February 2011

Abstract
PF-04691502 is a dual inhibitor of both PI3K and mTOR, inhibits PI3K signaling in cancer cell lines, and exhibits in vitro and in vivo anti-proliferative activity in PI3K-pathway driven cell lines. It is a nanomolar inhibitor of all 4 isoforms of the catalytic subunit of PI3K and of both TORC1 and TORC2. Anti-cancer activity of the inhibitor is hypothesized to be through inhibition of survival, proliferative, and anti-apoptotic processes. Its predicted human bioavalibility is roughly 60% and it will soon be entering phase 1 studies.
To provide an improved predictability of this compound and its PD markers in the clinic we correlated PK, PD (phosphoproteins and FDG-PET imaging) and tumor growth inhibition in a single model. Since this inhibitor exhibits an IC50 of 37 nM in the PC3 prostate cell line (PTEN null) in vitro we chose this cell line for a xenograft model. Three groups (Vehicle, 5 and 7.5 mg/kg.) were dosed p.o. daily and subsequently evaluated. Tissues were harvested on day 7 and 13 at 4.5 hr post-dose. FDG-PET imaging was completed on days 1, 3, 7 and 13 at 3 hr post-dose.
First, negative correlations were established between blood levels of PF-04691502 and the following tumor phosphoprotein epitopes: pS6, pAKTS473 and pAKTT308. The R2 values for these proteins were −0.3, −0.4 and −0.4, respectively. P-values of the correlations are all significant for all three proteins. Second, all PD markers were positively correlated with TGI. When correlating FDG-PET and TGI, day 7 has the best correlation and an R2 of 0.3 while days 3 and 13 have poorer correlations (R2 of 0.04 and 0.13, respectively). Although the R2 isn't high for day 7, the positive trend between image and TGI is statistically significant. When correlating PD markers and TGI, R2 values for pS6, pAKTS473 and pAKTT308 were 0.6, 0.8 and 0.6, respectively. In conclusion, the data from this single model indicates PD phosphoprotein markers are more reflective of TGI than FDG-PET imaging. These results will be applied to estimating the size of the cohort recruited for mechanistic evaluation in phase 1 trials of PF-04691502.
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 3492.
Abstract 3493: ON 01910. Na, a clinical trial stage multi-kinase inhibitor, induces apoptosis in chronic lymphocytic leukemia (CLL) cells through inhibition of PI3K/AKT and activation of the JNK pathway resulting in NOXA and BIM upregulation
Authors: Perez-Galan Patricia , Chapman Colby M. , Sun Xiameng , Gibellini Federica , Liu Poching , Raghavachari Nalini , Wiestner Adrian 
Published: February 2011

Abstract
Chronic Lymphocytic leukemia (CLL), the most common leukemia in Western countries, is a clinically heterogeneous disease characterized by the accumulation of mature B lymphocytes, where disease progression is driven by survival and proliferation signals provided by the tumor microenvironment. ON 01910. Na (Onconova Therapeutics) belongs to the family of styryl benzyl sulfones, a novel family of non-ATP competitive kinase inhibitors. ON 01910. Na is under clinical development in hematologic and solid tumors. Here we show that ON 01910. Na induced apoptosis in CLL samples (n=28) in vitro, without showing significant toxicity against T-cells or normal B-cells. Twenty four CLL samples were highly sensitive to ON 01910. Na (mean IC50=0.89 μM) a concentration readily achieved in phase I clinical trials, three showed moderate sensitivity (mean IC50=4.26 μM) and one was resistant (IC50 &gt;8 μM). There were no significant differences in ON01910. Na cytotoxicity against CLL cells expressing mutated (mean IC50=1.33 μM) or unmutated (mean IC50 =1.22μM) IgVH sequences. ON 01910. Na was similarly effective against tumor cells carrying 17p or 11q deletions. ON 01910. Na activated Bax and Bak, leading to mitochondrial depolarization. To delineate the upstream pathways underlying ON 01910. Na induced apoptosis, we performed Gene Expression Profiling (GEP) in CLL cells treated in vitro for 4 and 10 hours with ON 01910. Na. Gene Set Enrichment Analysis (GSEA) identified gene sets indicating BCR and PI3K inhibition (FDR&lt;0.2). In keeping with PI3K inhibition, we found that ON 19010. Na inhibited phosphorylation of Akt and Foxo3a, and FOXO3 target genes, including Bim, were upregulated. In addition, GSEA identified induction of AP-1 gene sets (FDR&lt;0.01) suggesting the generation of reactive oxygen species (ROS) by ON 01910. Na. Consistently, we found a rapid increase in ROS in cells treated with ON 01910. Na and ROS scavengers protected cells from its cytotoxic effect. ROS upregulated the proapoptotic BH3-only protein Noxa, and knockdown of Noxa by shRNA decreased the sensitivity to the drug by 60%. Our results identify ON 01910. Na as a promising agent in the treatment of CLL with an interesting dual mechanism of action: inhibition of the PI3K/AKT survival pathway with Foxo mediated upregulation of BIM and the induction of oxidative stress resulting in Noxa upregulation.
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 3493.
Abstract 3494: Experimentally validated modeling for optimizing therapeutic combinations of oncolytic adenoviruses and MEK inhibitor
Authors: Shiina Marisa , Bagheri Neda , Lauffenburger Douglas , Korn Wolfgang Michael 
Published: February 2011

Abstract
Oncolytic adenoviruses are therapeutic anti-cancer agents that selectively replicate in and lyse cancer cells motivating their use in targeted gene therapy. Successful entry of adenoviruses into target cells depends on attachment of the adenovirus fiber-knob protein to the Coxsackie-and Adenovirus Receptor (CAR), which is often down-regulated in highly malignant cells. In a previous study, we demonstrate that MEK inhibition may counter this effect by up-regulating CAR expression. In this study we optimize infection by investigating the combinatorial effect of oncolytic adenovirus infection and MEK inhibition through data-driven models and model-driven experiments. To motivate and test our hypotheses, we use HCT116 colon cancer cell line treated with MEK inhibitor, CI1040, and infected with oncolytic adenoviruses, ONYX-015, Delta-24 and Delta-24RGD. We developed a nonlinear ordinary differential equation model that characterizes the dynamics of these cancer cells subject to ONYX-015 infection modulated by CI1040. Resulting simulations offer predictions that may help guide experimental design and inform optimal timing of CI1040 treatment and ONYX-015 infection to minimize cancer growth. Experimental results demonstrate that HCT116 cells treated with CI1040 for 2 days and infected with adenoviruses have stronger cytopathic effects, greater virus uptake, and greater production when compared to the DMSO control. We also found that G1 cell cycle arrest, caused by CI1040 treatment, is associated with increased virus production. To assess the role of release from cell cycle arrest as a mechanism leading to enhanced production of oncolytic adenoviruses, we synchronize cells by density arrest for 48 hours, release and infect with adenoviruses. The results showed a more potent cell killing effect and virus production on cells arrested in G1 and released. We expanded our analysis to a panel of 21 pancreatic cell lines, as this tumor type is a possible target for adenoviral therapies. Enhanced virus replication and cell killing were observed in different pancreatic cell lines, suggesting that combination therapy of CI1040 and oncolytic adenoviruses have potential implications for the design of future clinical trials and improved oncolytic adenoviruses therapies.
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 3494.
Abstract 3498: The cytotoxicity and genotoxicity of etoposide and other phenolic and non-phenolic agents in human myeloid leukemia HL-60 cells: role of myeloperoxidase (MPO)
Authors: Yalowich Jack C. , Hornbaker Marisa , Bodnar Andrew J. , Jin ShunQian , Zhang Yuxun , Day Billy W. , Fuchs James R. , Li Pui-Kai 
Published: February 2011

Abstract
The clinical efficacy of the anticancer agent etoposide (VP-16) is compromised by its ability to cause acute myeloid leukemias (t-AML) associated with MLL gene rearrangements. We proposed previously that myeloperoxidase (MPO) found in myeloid precursors converts the phenolic drug VP-16 to its phenoxyl radical (VP-16-O[[Unable to Display Character: &#8729;]]), which redox cycles, leading to the generation of reactive oxygen species, oxidative DNA damage linked to DNA topoisomerase II (topo II)-mediated strand cleavage, and resultant recombination events causal for t-AML. After knockdown with an shRNA for MPO in myeloid leukemia HL-60 cells, MPO activity was reduced to 13% of shRNA controls. In these MPO knockdown cells, VP-16-O[[Unable to Display Character: &#8729;]] formation and VP-16-induced topo II/DNA covalent complexes were reduced compared to shRNA controls demonstrating that VP-16 activity was, in part, dependent on MPO. MPO can also oxidize VP-16 to its ortho-quinone metabolite which is subsequently inactivated by conjugation with glutathione. The cytotoxicities of VP-16, curcumin (a phenolic agent), and a curcumin analog (FLLL-10) were increased in MPO knockdown cells compared to shRNA controls. Podophyllotoxin, the non-phenolic VP-16 parental compound, was equally cytotoxic in MPO knockdown and control cells. Additionally, the cytotoxicity of hydrogen peroxide, an MPO co-substrate, was unaffected by MPO levels. Results indicate that MPO converts VP-16 to a pro-oxidant, which leads to genotoxicity, while simultaneously protecting cells from drug-induced cytotoxicity likely by glutathione conjugation to VP-16 ortho-quinone. The combined results suggest a mechanism by which MPO-containing myeloid progenitor cells can be relatively protected against VP-16-induced apoptosis/cytotoxicity while suffering increased genotoxic and recombinogenic insults responsible for leukemogenesis. Support: NIH CA090787.
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 3498.
Abstract 35: Metabolomic analysis of MCF-7 and MCF-10 cells after thiaminase I exposure
Authors: Richardson Adam D. , Liu Shuqian , Moscow Jeffrey A. 
Published: February 2011

Abstract
We have recently shown that recombinant thiaminase I enzyme has cytotoxic activity against breast cancer cell lines (Liu, S., Monks, N.R., Hanes, J.W., Begley, T.P., Yu, H. and Moscow, J.A. Sensitivity of breast cancer cell lines to recombinant thiaminase I. Cancer Chemotherapy and Pharmacology, 2009). Because thiamine is a cofactor in several key metabolic enzymes, including pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase and transketolase, information regarding the metabolic consequences of thiaminase I treatment may increase our understanding of the cytotoxic mechanism-of-action of thiaminase I. We analyzed the metabolomes of the MCF-7 breast cancer cell line and the immortalized but non-malignant breast cell line MCF-10A with or without incubation for 4 days in medium containing thiaminase I at the predetermined cytotoxic IC50 concentrations (0.125 U/ml for MCF-7 and 0.25 U/ml for MCF-10A), with the addition of [U-13C]-labeled glucose in the final 2 days. By tracking the metabolism of [U-13C]-glucose using GCMS and NMR we were able to quantify intracellular metabolite pools and calculate both relative and absolute flux rates through several key pathways. Thiaminase I treatment decreased the amount of protein per MCF-7 cell by 30% (163 pg/cell to 115 pg/cell) while the total protein remained essentially unchanged in the MCF-10A cells (141 pg/cell vs 152 pg/cell). While both cell lines displayed increased glucose consumption and lactate production during thiaminase I treatment, these responses were greater in the MCF-7 cell line. Metabolite analysis revealed significant alterations to glycolysis and the TCA cycle in both cell lines, with glycolysis-linked metabolites being depleted in the MCF-7 cell line and changes in the equilibrium of TCA cycle intermediates in the MCF-10A cell line. The 13C- labeling patterns suggest that the MCF-10A cell line responds to thiaminase I treatment by increasing the catabolism of alternate, non-glucose carbon sources through the activation of specific metabolic pathways. In contrast, the MCF-7 cell line appears to have a less adaptable metabolic program and must down-regulate its overall metabolic throughput. Therefore, the possibility is raised that differential metabolic effects of thiaminase I could be exploited therapeutically.
Supported by the Susan G. Komen For the Cure Foundation (JAM) and the California Breast Cancer Research Program (ADR).
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 35.
Abstract 3502: Understanding the pathways involved in the repair of CNDAC induced DNA damage
Authors: Frame Sheelagh , Armour Sian , Munro Clare , Hogben Morag , Jones Ruth , Blake David G. , MacCallum David E. , Green Simon R. 
Published: February 2011

Abstract
CNDAC is the active metabolite of sapacitabine, which is currently being evaluated in Phase II clinical trials for acute myeloid leukaemia, myelodysplastic syndrome and non small cell lung cancer. CNDAC (2′-C-Cyano-2′-deoxy-β-D-arabino-pentafuranosylcytosine) was designed as a novel cytosine analogue with a unique mechanism of action. The presence of the cyano-group within the ribose moiety of the molecule causes the formation of single-stranded DNA strand breaks, following incorporation of CNDAC into an extending DNA chain. These breaks are difficult to repair and are processed into double-strand DNA breaks that activate the dsDNA damage checkpoint. As a consequence of this unique mechanism of action, CNDAC arrests cells in the G2/M phase of the cell cycle in contrast to other nucleoside agents such as cytarabine and gemcitabine which cause an S-phase arrest. As such CNDAC may have unique therapeutic applications as a single agent in certain tumour types as well as in combination with other agents compared with standard nucleoside analogues.
In order to identify options for maximising that activity of CNDAC, two approaches were taken to evaluate the repair mechanisms involved for CNDAC induced DNA damage. First a small scale siRNA screen was used to identify genes that were synthetically lethal with CNDAC. Ten targets were initially selected; prioritising genes known to be involved in DNA repair and including BRCA, ATM, CHK and ERCC1. The most dramatic increase in CNDAC sensitivity was seen when BRCA2 was targeted by siRNA, indicating that the homologous recombination DNA repair pathway is involved in the repair of CNDAC induced DNA damage. The second approach involved a cytotoxicity screen evaluating synergy with commercially available agents that either target DNA repair or induce DNA damage themselves. The most promising combinations were then followed up with flow cytometry analysis to examine the induction of cell death. Using this approach the best synergy was detected between CNDAC and either the ATM inhibitor, KU55933 or the CHK inhibitor PF477736. Again these data indicate that the homologous recombination pathway is involved in the repair of CNDAC induced DNA damage.
These data suggest that it would be feasible to explore the clinical use of sapacitabine in diseases where the homologous recombination DNA repair pathway is compromised, such as BRCA deficient tumours. Data from these ongoing studies will be presented.
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 3502.
Abstract 3507: Facilitating pixantrone-induced DNA damage and subsequent cell kill through formaldehyde activation and improvements in drug design
Authors: Evison Benny J. , Mansour Oula C. , Sleebs Brad E. , Watson Keith G. , Rephaeli Ada , Nudelman Abraham , Phillips Don R. , Cutts Suzanne M. 
Published: February 2011

Abstract
Pixantrone is a novel aza-anthracenedione originally developed to improve the therapeutic profile of mitoxantrone, a DNA-interactive agent currently used in the clinical management of a range of haematological malignancies and solid tumours. Like mitoxantrone, pixantrone interacts with DNA via intercalation and stimulates topoisomerase II-mediated DNA cleavage, presumably by stabilising the cleavable complex. Despite the drug's ability to stimulate DNA cleavage via topoisomerase II impairment, this form of DNA damage does not directly correlate with drug cytotoxicity, suggesting that pixantrone may be operating by a distinct, currently undefined mechanism of cell kill. A novel form of pixantrone-DNA interaction has recently emerged in which the drug can be efficiently activated by formaldehyde to yield covalent drug-DNA adducts. In cellular systems, pixantrone exhibits a mild synergistic relationship with the formaldehyde-releasing prodrug AN-9, indicating a favourable role for formaldehyde in mediating pixantrone-induced cell kill. A variety of methods including in vitro transcription and mass spectrometry have established that formaldehyde-activated pixantrone is a monofunctional DNA alkylator that binds selectively to CpG and CpA dinucleotides via the exocyclic N2 amino group of guanine within DNA. Crucially, formaldehyde provides the methylene bridge that covalently links DNA with a single drug side-chain. A major functional limitation of the monoadduct is its poor intrinsic stability (t1/2 = 75 min). It was subsequently rationalised that an increase in drug side-chain length may permit the drug to completely bridge the two strands of duplex DNA, much like an interstrand crosslink. Accordingly, new anthracenediones were synthesised that incorporated symmetrical side chains of the nature -NH-(CH2)n-NH2 (where n = 2—5). An in vitro crosslinking assay demonstrated that side-chain extension generally conferred a remarkable increase in the temporal stability of formaldehyde-activated anthracenedione-DNA adducts. A clear and direct relationship existed between side-chain length and drug-DNA adduct half-life with MX5 (n = 5) exhibiting exceptional stability (t1/2 &gt; 2 days). Significantly, the enhanced drug-DNA adduct stability was reflected in breast adenocarcinoma MCF-7 cells where derivatives with longer side-chains were synergistic in combination with the formaldehyde-releasing prodrug AN-9.
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 3507.