bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4482: Pemetrexed treatment results in DNA replication fork instability and double strand breaks formation in UNG-/- human cancer cells.
Authors: Weeks Lachelle D. , Zentner Gabriel , Scacheri Peter , Gerson Stanton L. 
Published: August 2014

Abstract
Misincorporation of genomic uracil and formation of DNA double strand breaks are known consequences of exposure to TS inhibitors such as 5-fluorouracil, and pemetrexed. Uracil DNA glycosylase catalyzes the excision of genomic uracil and initiates DNA base excision repair (BER). Thus, a relationship between antifolate cytotoxicity and UNG expression and activity has been hypothesized. However, a precise mechanism linking antifolate-induced formation of DSBs to genomic uracil accumulation and UNG-initiated BER has not been described. Herein, we report that despite equivalent proliferation indices, DLD1 UNG-/- cells are more sensitive to pemetrexed mediated intra S-phase arrest, DNA double strand break formation and apoptosis compared to UNG+/+ cells. Using data from western blots in chromatin extracts, PCNA staining of cells in S-phase, and pulse-chase labeling of replicating cells with CldU and IdU, we surmise that the accumulation of uracil in pemetrexed-treated UNG-/- cells is associated with significant replication fork instability. In addition, UNG-/- cells have reduced capacity to recover from pemetrexed-mediated DNA damage, as indicated by the persistence of S-phase arrest and gamma-H2AX foci. This defect in recovery was not explained by double strand break repair capacity, which was equivalent in UNG+/+ and UNG-/- cells. Using γ-H2AX ChIP sequencing, we observed a 5-fold increase in the number of γ-H2AX binding sites in UNG-/- cells compared to UNG+/+ cells treated at IC50 levels of pemetrexed. This analysis evinced distinct patterns of γ-H2AX binding in UNG+/+ and UNG-/- cells. Double strand breaks (γ-H2AX) were more significantly associated with transcription start sites and putative origins of replication in UNG-/- cells compared to UNG+/+ cells. Based on these data we conclude that uracil accumulation, and thus UNG activity, during pemetrexed exposure directs both the quantity and the location of double strand breaks. These findings support uracil mediated S-phase arrest and DNA replication fork collapse as the mechanism of double strand break formation and cell death in pemetrexed treated UNG-/- cells.
Citation Format: Lachelle D. Weeks, Gabriel Zentner, Peter Scacheri, Stanton L. Gerson. Pemetrexed treatment results in DNA replication fork instability and double strand breaks formation in UNG-/- human cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4482. doi:10.1158/1538-7445.AM2013-4482
Abstract 4484: Uracil DNA glycosylase expression determines human lung cancer cell sensitivity to pemetrexed.
Authors: Weeks Lachelle D. , Fu Pingfu , Liu Lili , Gerson Stanton L. 
Published: August 2014

Abstract
Uracil misincorporation into DNA is a consequence of pemetrexed inhibition of thymidylate synthetase (TS). The DNA base excision repair (BER) enzyme, uracil DNA glycosylase (UNG) is the major glycosylase responsible for removal of misincorporated uracil. We previously illustrated hypersensitivity to pemetrexed in UNG-/- human colon cancer cells (DLD1) and proposed that cytotoxic uracil accumulation leads to collapsed replication forks, double strand breaks and cell death. Here, we examined the relationship between cellular capability to remove uracil-DNA and pemetrexed sensitivity in human lung cancer cells. Viral siRNA and shRNA knockdown of UNG enhanced pemetrexed sensitivity in A549 and H1975 cells, respectively. We further evaluated induction of UNG as a mechanism of pemetrexed resistance. Exposure of H1299 cells to step-wise increasing concentrations of pemetrexed established drug resistant sublines: H1299PR-1 and H1299PR-2. Significant induction of UNG protein was observed in both sublines. Importantly, co-treatment with the BER inhibitor, methoxyamine (MX), overcame pemetrexed resistance in H1299PR-1/2 underscoring the utility of BER directed therapeutics to offset acquired pemetrexed resistance. Lastly, differential expression of UNG in cell lines and primary lung cancer tissues was associated with pemetrexed sensitivity. Cell lines derived from squamous and small cell carcinoma, known to be clinically resistant to pemetrexed, had the highest levels of UNG expression in a panel of eight lung cancer cell lines. Analysis of cDNA microarrays derived from primary human lung cancer tissues also indicated high UNG expression in pemetrexed-resistant histological subtypes. Thus, we propose that UNG is a major determinant of pemetrexed sensitivity in human lung cancer.
Citation Format: Lachelle D. Weeks, Pingfu Fu, Lili Liu, Stanton L. Gerson. Uracil DNA glycosylase expression determines human lung cancer cell sensitivity to pemetrexed. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4484. doi:10.1158/1538-7445.AM2013-4484
Abstract 4487: Synergistic effects of resveratrol and doxorubicin on inducing the apotosis of mouse and human PTEN deficient T-cell acute lymphoblastic cells.
Authors: Chen Ling , Yang Yaling , You M. James 
Published: August 2014

Abstract
Resveratrol (3,5,4’-trihydroxy-trans-stilbene), a plant antibiotic produced in a wide variety of plants in response to stress, injury, UV irradiation, and fungal infection, has been shown to inhibit cell growth of several types of cancer. The aim of the present study was to determine the effects of Resveratrol alone and its combination with Doxorubicin, a commonly used chemotherapeutics for T-cell acute lymphoblastic leukemia (T-ALL), on the proliferation and apoptosis of T-ALL cells. Mouse T-ALL cell lines were derived from T-cell-specific deletion of Pten tumor suppressor gene, and human T-ALL cells were obtained from ATCC. We treated T-ALL cells with different concentrations of Resveratrol (0 μM to 200 μM) alone and in combination with various concentrations of Doxorubicin (0 μM to 1 μM) for different durations (0, 12, 24, 48 and 72 hours, respectively). We showed mouse and human Pten deficient T-ALL cell lines were sensitive to the treatment of Resveratrol in dose- and time-dependent manners. In addition, low dose Resveratrol (3.125 μM) in combination with very low dose of o (0.01 μM) showed a remarkable synergistic effect on the cell proliferation and apoptosis. Flow cytometric analysis with Annexin V and Western blot studies on Caspase 3 confirmed that Resveratrol induced apoptosis, especially in combination with Doxorubicin. This study establishes a potential role of Resveratrol in the treatment of Pten deficient T-ALL.
Citation Format: Ling Chen, Yaling Yang, M. James You. Synergistic effects of resveratrol and doxorubicin on inducing the apotosis of mouse and human PTEN deficient T-cell acute lymphoblastic cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4487. doi:10.1158/1538-7445.AM2013-4487
Abstract 4488: A synergistic effect between aldehydes and doxorubicin in S. cerevisiae provides a model for enhancing anthracycline-based therapy.
Authors: Miles Jana S. 
Published: August 2014

Abstract
We have previously reported that interruption of the synthesis of the amino acid threonine confers sensitivity to doxorubicin in S. cerevisiae. Threonine synthesis requires the genes HOM6, THR1, and THR4, which encode the enzymes homoserine dehydrogenase, homoserine kinase, and threonine synthase, respectively. The inactivation of these genes in threonine biosynthesis results in increased toxicity of doxorubicin. Interestingly, the most sensitive strain, hom6, results in the accumulation of L-aspartate semialdehyde. We hypothesize that the accumulation of this metabolite results in toxic synergy with doxorubicin.
We have further investigated the role of aldehydes in the sensitization of yeast cells to anthracyclines. Inactivation of HOM3, which encodes for the aspartate kinase required for the first step in threonine biosynthesis, prevents the accumulation of the L-aspartate semialdehyde in the hom6 strain and rescues its sensitivity to doxorubicin, suggesting a role for the aldehyde in the sensitization to doxorubicin. Furthermore, wild type strains treated with different aldehydes significantly reduced the survival of the cells to anthracyclines, and distinctly in other therapeutic agents. These results indicate that aldehydes have a synergistic effect with anthracyclines. In humans, threonine is an essential amino acid and its biosynthesis does not occur. However, our results are directly applicable to relevant human pathways in nonessential amino acids and ornithine synthesis. Potential application of the accumulation of glutamic semialdehyde and succinic semialdehyde intermediates for a synergistic effect with doxorubicin is discussed.
Research supported by NIH/NCRR RCMI grant #RR03020 at Florida A&M University.
Citation Format: Jana S. Miles. A synergistic effect between aldehydes and doxorubicin in S. cerevisiae provides a model for enhancing anthracycline-based therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4488. doi:10.1158/1538-7445.AM2013-4488
Abstract 4496: Differential inhibition by microtubule stabilizing agents of 2-(m-azidobenzoyl)Taxol photoaffinity labeling of tubulins from different eukaryotic sources.
Authors: Yang Chia-Ping H. , Xiao Hui , Horwitz Susan Band 
Published: August 2014

Abstract
Distinct α- and β-tubulin isotypes are present in different quantities in diverse eukaryotic cells. The tritium-labeled photoaffinity Taxol analog, 2-(m-azidobenzoyl)Taxol, was used to photolabel tubulins prepared from HeLa cells, bovine brain and chicken erythrocytes. A 5-fold molar excess of unlabeled compound inhibited the photolabeling of tubulin by &gt;90%, demonstrating the specificity of this photolabeling. Tubulin isotype content varies from one source to another, particularly for chicken erythrocytes that contain only one α-tubulin and one β-tubulin (α1 and βVI). 2-(m-azidobenzoyl)Taxol photoaffinity labeling of tubulin was carried out in the presence of six different microtubule stabilizing agents, including Taxol, epothilone B, discodermolide, ixabepilone, laulimalide and peloruside A. The inhibitory effects elicited by Taxol, epothilone B, discodermolide and ixabepilone, at a 5-fold molar excess, on photolabeling are different for tubulins prepared from different sources. Taxol had a minimal inhibitory effect on HeLa and bovine brain tubulin, but a strong inhibitory effect on chicken erythrocyte tubulin. Discodermolide exhibited opposite effects on photolabeling, compared to those of Taxol. This is most likely due to the presence of distinct tubulin isotypes in different sources. However, laulimalide and peloruside A that are known to bind to a different site than Taxol in β-tubulin, stimulated photolabeling of tubulins from all three sources. Stathmin (S) plays an important role in the regulation of microtubule dynamics through sequestering tubulin (T) into a T2S complex. When stathmin was incubated, in the presence of 1 mM CaCl2, with chicken erythrocyte tubulin at a tubulin:stathmin ratio of 2:1, followed by incubation with tritium-labeled 2-(m-azidobenzoyl)Taxol in a buffer containing EGTA, photolabeling of β-tubulin was markedly reduced, suggesting that stathmin inhibited binding of Taxol to tubulin. Radiolabeled photoaffinity drug analogs are useful tools for determining drug binding affinities for the different tubulin isotypes. We are currently analyzing binding affinities of 2-(m-azidobenzoyl)Taxol to different bovine brain tubulin isotypes resolved by isoelectrofocusing.
Citation Format: Chia-Ping H. Yang, Hui Xiao, Susan Band Horwitz. Differential inhibition by microtubule stabilizing agents of 2-(m-azidobenzoyl)Taxol photoaffinity labeling of tubulins from different eukaryotic sources. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4496. doi:10.1158/1538-7445.AM2013-4496
Abstract 4505: Preparation and anti-tumor growth of polyethylene glycol-poly lactic acid block copolymers sorafenib nanoparticles.
Authors: Qin Jianmin 
Published: August 2014

Abstract
BACKGROUND&AIMS: In vitro and in vivo studies have showed that sorafenib can inhibit the growth of liver cancer cells and solid tumor. However, poor water solubility, short half-life, high side-effect limit its clinical application in malignant tumor treatment. In this study, we report on the preparation of sorafenib nanoparticles by nanotechnology, and to observe the anti-hepatocarcinoma effect and in vivo metabolism of sorafenib nanoparticles. Methods:Polyethylene glycol-poly lactic acid block copolymers were synthesized with ring-opening polymerization technique as drug carrier material. Polyethylene glycol-poly lactic acid block copolymers sorafenib nanoparticles were prepared with nanometer precipitation method. The particle diameter and surface potential of sorafenib nanoparticles were determined by nanometer particle size and zeta otentiometer(Nano-ZS ZEN3600, Malvern). Drug-loading rate and entrapment rate were determined by ultraviolet spectrophotometer. In vitro slow release of sorafenib nanoparticles was determined by extracorporeal dialysis. The effect of sorafenib nanoparticles on H22 liver cancer cells proliferation was determined with CCK8 reagent in vitro culture .In vivo pharmacokinetics of sorafenib nanoparticles was analysed with DAS2.1.1 software. Results:Sorafenib nanoparticles were round, particle diameter was 127.3±2.0 nm, Zeta potential was -3.35±0.42 mV, drug-loading rate was 6.78%, entrapment rate was 98.21%. In vitro accumulative release rate of sorafenib nanoparticles at 24h, 48h, 72h, 96h were respectively 50.9073%, 56.2395%, 60.2561%, 63.2843%. The inhibitive effect of sorafenib nanoparticles on H22 liver cancer cells proliferation was more enhanced than that of sorafenib at the same drug concentration(F=74.988,P&lt;0.05), The inhibitive effect of sorafenib nanoparticles on H22 liver cancer cells proliferation enhanced at the increase of sorafenib concentration. The in vivo metabolism time of sorafenib in sorafenib nanoparticles group was longer than that of sorafenib group (SNP t1/2, 13.95h vs S t1/2, 9.67h; t=2.618, P&lt;0.05). Conclusion:Sorafenib nanoparticles can significantly inhibit the cells proliferation of liver cancer, and prolong in vivo metabolism of srafenib. The preparation of sorafenib nanoparticles has established good theoretical basis to further study in vivo anti-tumor effect and mechanism of sorafenib nanoparticles .
Citation Format: Jianmin Qin. Preparation and anti-tumor growth of polyethylene glycol-poly lactic acid block copolymers sorafenib nanoparticles. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4505. doi:10.1158/1538-7445.AM2013-4505
Abstract 4507: Utilizing the targeting properties of elastin-like polypeptide to safely deliver a potent doxorubicin derivative.
Authors: Walker Leslie R. , Perkins Eddie , Abu Ajaj Khalid , Kratz Felix , Raucher Drazen 
Published: August 2014

Abstract
N-butyldiacetate doxorubicin (NBD) is a derivative of a common chemotherapeutic agent that is three to four orders of magnitude more potent that the its parent compound. Targeting such a potent drug to the tumor, relies on an effective tumor targeting strategy. For this purpose, we have developed a hypothermic approach and developed a new macromolecular conjugate by coupling NBD to elastin-like polypeptide (ELP), a macromolecule that is soluble at normal physiological temperature but aggregates in the presence of heat (40-42 °C). Attaching NBD to ELP holds the promise of accumulating NBD effectively in the tumor while sparing healthy tissue. ELP is a macromolecule that is soluble at normal physiological temperature but aggregates in the presence of heat (40-42 °C). The ELP delivery system, SynB1-ELP-NBD, consists of 3 parts: a) a cell-penetrating peptide to facilitate entry through the cell membrane, b) ELP to allow thermal targeting, and c) an acid-sensitive derivative of doxorubicin, NBD. Preliminary results in the S2013 pancreatic cancer cell line have been promising. The IC50 of free doxorubicin is ∼9 μM, while the IC50 of SynB1-ELP-NBD is 1 nM. Very little is known about the mechanism of NBD inside the cell. Using flow cytometry, we compared apoptosis, cell cycle arrest, and generation of reactive oxygen species of SynB1-ELP, SynB1-ELP-NBD, and free NBD. While SynB1-ELP had very little effect on the cell cycle, generation of ROS, and less than 10% apoptotic cells, SynB1-ELP-NBD and free NBD were more active during the S phase at the expense of G1, generated 6× more ROS compared to control cells, and 80% of cells were apoptotic or necrotic after 72 h treatment. In vitro, SynB1-ELP-NBD works very similarly to free NBD, but safe delivery is the goal. In a maximum tolerated dose study, the animals were able to tolerate 2.5 times more NBD when it was attached to ELP compared to free NBD. This delivery system makes it possible to deliver larger amounts of a highly potent doxorubicin derivative to tumor-bearing animals and a comparative in vivo study in a pancreatic cancer mouse model is ongoing.
Citation Format: Leslie R. Walker, Eddie Perkins, Khalid Abu Ajaj, Felix Kratz, Drazen Raucher. Utilizing the targeting properties of elastin-like polypeptide to safely deliver a potent doxorubicin derivative. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4507. doi:10.1158/1538-7445.AM2013-4507
Abstract 4509: Genetically encoded chimeric polypeptide nanoparticles for paclitaxel delivery to triple negative breast cancer.
Authors: Bhattacharyya Jayanta , McDaniel Jonathan , Chilkoti Ashutosh 
Published: August 2014

Abstract
Triple negative breast cancer (TNBC) represents an important clinical challenge, because TNBC, like other breast cancer subtypes is highly metastatic, but TNBC displays a shorter median time to relapse and death. Chemotherapy remains the mainstay of treatment of TNBC, as it gives a markedly higher response rate than endocrine therapy or other available targeted agents. Current treatment strategies for TNBC include treatment with anthracyclines, taxanes, and platinates. Like other drugs, paclitaxel shows a lack of selectivity towards tumor cells, sub-optimal pharmacokinetics and bio-distribution, leading to limited efficacy and significant systemic toxicity. Although AbraxaneTM (albumin bound paclitaxel) an improved formulation of paclitaxel compared to the original chremophor formulation has been used to treat TNBC, it also suffers from systemic toxicity such as sensory neuropathy, neutropenia, nausea, and anemia.
In an effort to overcome the limited efficacy and systemic toxicity of current paclitaxel formulations, we have designed a novel polypeptide drug delivery system where paclitaxel is covalently attached to a genetically engineered chimeric polypeptide (CP) through a pH sensitive linker such that covalent conjugation of multiple copies of Paclitaxel at one end of the CP spontaneously triggers the self-assembly of the drug-CP conjugate into sub 100 nm size nanoparticles that are ideal for targeting solid tumors through the enhanced permeability and retention (EPR) effect.We found that in a human triple negative breast cancer cell (MDA-MB-231), the CP-paclitaxel conjugate showed substantial cytotoxicity that was similar to free drug. CP-Paclitaxel nanoparticle treated mice with orthotopic MDA-MB-231 tumors showed significantly greater tumor regression as well as enhanced overall survival compared to free drug. These results are promising because they demonstrate the potential of rationally engineered nanoparticle drug carriers to greatly improve the efficacy of currently approved cytotoxic agents for the treatment of solid tumors. In future work, we will evaluate the efficacy of CP-Paclitaxel nanoparticles combined with a tyrosine kinase inhibitor that mimics current combination chemotherapy.
Citation Format: Jayanta Bhattacharyya, Jonathan McDaniel, Ashutosh Chilkoti. Genetically encoded chimeric polypeptide nanoparticles for paclitaxel delivery to triple negative breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4509. doi:10.1158/1538-7445.AM2013-4509
Abstract 4529: Self-assembled lipid-polymer hybrid nanoparticles for the sustained delivery of siRNA and the treatment of drug-resistant cancers.
Authors: Shi Jinjun , Xu Yingjie , Xu Xiaoyang , Votruba Alexander , Zhu Xi , Pridgen Eric , Xiao Zeyu , Langer Robert , Zetter Bruce R. , Farokhzad Omid C. 
Published: August 2014

Abstract
RNA interference (RNAi), which can selectively knockdown target genes, has shown great potential in the treatment of various diseases including cancer. Thus far, numerous nanoparticle (NP) platforms such as lipoplex and polyplex have been developed to facilitate the safe and effective delivery of small interfering RNA (siRNA), which represents a major hurdle for the clinical applications of RNAi. Nevertheless, these NP systems lack the sustained siRNA release property, and thus can only induce transient gene silencing due to the short lifetime of siRNA. Therefore, the delivery of siRNA using controlled-release NPs would be necessary for achieving sustained gene silencing.
Herein, we will present a novel NP platform for safe and effective siRNA delivery in a sustained manner, which can be developed through the self-assembly of biodegradable and biocompatible polymers and lipids. The lipid-polymer hybrid NPs show excellent in vitro knockdown efficacy at low doses of siRNA, and promising in vivo results for delivering siRNA to xenograft tumors. More importantly, these NPs can control the temporal release of siRNA, with the half-release time of ∼ 9 days, for sustained silencing of target gene expression. Results demonstrate that the luciferase expression is still less than 25% at day 7 when the lucifrease-expressed HeLa cells were transfected with the NPs containing 40 pmol anti-luciferase siRNA. As a comparison, the luciferase expression is largely recovered (∼ 80%) at day 7, after transfection with lipo2000-siRNA complexes. Furthermore, this NP platform has been applied to deliver anti-drug resistance siRNA (e.g., anti-PHB1) and chemotherapeutic drugs (e.g., taxanes) for the effective treatment of drug resistant cancers. We believe that the lipid-polymer hybrid NP platform with the property of sustained siRNA release could hold potential in both fundamental studies and clinical applications.
Citation Format: Jinjun Shi, Yingjie Xu, Xiaoyang Xu, Alexander Votruba, Xi Zhu, Eric Pridgen, Zeyu Xiao, Robert Langer, Bruce R. Zetter, Omid C. Farokhzad. Self-assembled lipid-polymer hybrid nanoparticles for the sustained delivery of siRNA and the treatment of drug-resistant cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4529. doi:10.1158/1538-7445.AM2013-4529