bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2655: Apoptotic peptide hybrid for treatment of chemotherapy-resistant cancers
Authors: Kim Ji-seon 
Published: February 2011

Abstract
Resistance to chemotherapy is one of the major obstacles to successful cancer treatment. Many cancer patients develop metastatic cancers after responding to initial treatment, which are often refractory to chemotherapy, and remain incurable. Inhibition of apoptotic pathways due to up-regulation of anti-apoptotic elements, such as Bcl-2 and IAPs (inhibitors of apoptosis proteins) has been reported to account for the resistance to chemotherapeutic agents. Thus, it is critical to restore the inhibited apoptosis to re-sensitize the cancer to chemotherapy. In this study, we investigated whether a pro-apoptotic peptide and a proteasome inhibitor peptide can synergize to induce apoptosis in doxorubicin-resistant cancer cells in vitro. The pro-apoptotic peptide is a cationic amphipathic peptide which depolarizes mitochondrial membranes to release apoptosis initiators such as, cytochrom c and Smac/DIABLO to cell cytosols, which activate caspases, apoptosis executors by inhibiting IAPs (inhibitors of apoptosis proteins). MG132 (Z-Leu-Leu-Leu-CHO) has been reported to inhibit anti-apoptotic proteins including NF-[[Unable to Display Character: &#312;]]B and Bcl-2 family proteins to stimulate apoptosis. We hypothesized that when concurrently delivered to the same cells, KLA and MG132 would synergize to induce apoptosis in resistant cancer cells by acting on different stages of apoptotic pathways. To test this, we conjugated KLA and MG132 by forming acid-labile Schiff bases between ε-amino groups of lysines in KLA and the aldehyde group of MG132. We expected that the formed KLA-MG132 conjugates would be internalized into cells by pinocytosis then, dissociated in the acidic environment (pH 4 – 5) of lysosomes to release intact KLA and MG132. The conjugation efficiency was found to be ∼ 100%, as measured indirectly by quantifying amine groups of un-conjugated lysine residues by TNBS assay. The conjugation was confirmed further by determining the molecular masses of the formed conjugates by mass spectrometry after reducing the conjugates by NaBH4 to stabilize Schiff bases. The conjugates induced upto 50 % of cell death in doxorubicin-resistant human cancer cells at the concentration of 0.6 μM as determined by MTT assay meanwhile; un-conjugated MG132 and KLA were inactive at the same concentration. And, the levels of cytosolic cytochrome c were 2-fold greater in the cells treated with KLA-MG132 conjugates than in cells treated with MG132 alone. The levels of active caspase-3 were higher by up to 70 % in cells treated with KLA-MG132 conjugate than in cells treated with MG132 alone. In conclusion, we have observed that KLA and MG132 conjugated via Schiff base induced potent apoptosis in doxorubicin-resistant human cancer cell lines at sub-micromolar concentrations.
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 2655.
Abstract 2659: A thermally targeted carrier of p50 NLS peptide inhibits cancer cell proliferation by preventing NFκB nuclear translocation
Authors: Thomas Emily H. , Raucher Drazen 
Published: February 2011

Abstract
The application of rationally designed therapeutic peptides may improve outcomes in cancer treatment. These peptides hold the potential to directly target proliferative pathways and to inhibit their over-expression. The NFκB survival pathway is constitutively active in many cancers and plays a role in evading apoptosis. A p50 NLS-derived peptide has been shown to bind to the nuclear receptor and prevent NFκB translocation into the nucleus. This 10 amino acid peptide thus inhibits the transcriptional activation of NFκB's cellular targets that are implicated in cancer cell survival and metastasis.
By conjugating the p50 derived peptide to a thermally targeted carrier and a cell penetrating peptide, the specificity and stability of peptide delivery can be enhanced. The addition of a cell penetrating peptide, SynB1, to the N-terminus of ELP enhances the cellular uptake of the conjugated peptide, SynB1-ELP1-p50. Elastin like polypeptide (ELP) is an elastin derived biopolymer that undergoes a thermally-mediated phase transition. By applying an external heat source, mild hyperthermic conditions (41°C) can induce aggregation and therefore can be used to specifically target ELP to solid tumors in cancer therapy. Uptake studies indicate that hyperthermia increases the accumulation of flourescein-labeled SynB1-ELP1-p50 in MCF-7 cells by 3 fold as compared to SynB1-ELP1-p50 treatment without heat. In addition to providing a level of targeting specificity, as a macromolecule, ELP may increase the plasma stability of small therapeutic peptides, like p50, and therefore creates the potential for viable delivery in vivo.
Preliminary in vitro studies have demonstrated that two 1-hour treatments with 20μM of SynB1-ELP1-p50 inhibits cell proliferation by 20% and in combination with hyperthermia by 40%, in both MCF-7 and HeLa cell lines. No inhibitory effect was seen when the carrier control, SynB1-ELP1, was used. Confocal microscopy studies illustrate the predominantly cytoplasmic localization of rhodamine labeled SynB1-ELP1-p50 with some localization at the nuclear periphery. Immunofluorescence studies suggest that SynB1-ELP1-p50 may attenuate the nuclear translocation of NFκB following stimulation with TNF-α. Future studies will elucidate the anti-proliferative mechanisms of this conjugated peptide and quantify the inhibition of nuclear translocation of NFκB following treatment with SynB1-ELP1-p50.
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 2659.
Abstract 2667: Inhibition of CYP3A4 expression by camptothecin via blocking activation of pregnane X receptor
Authors: Chen Yakun , Tang Yong , Robbins Gregory Thomas , Nie Daotai 
Published: February 2011

Abstract
Individual variation in drug metabolism is a major cause of unpredictable side effects during cancer therapy. Drug metabolism is controlled by a class of orphan nuclear receptors (NRs), which regulate the expression of cytochrome 3A4 (CYP3A4), an enzyme metabolizing more than 60% of clinically used drugs. In our study, it was found that xenobiotic-mediated induction of CYP3A4 gene expression in primary human hepatocytes was inhibited by camptothecin (CPT) but not by its analogue, irinotecan (CPT-11). CPT exerted its effect by inhibiting the activation of NR, human pregnenolone X receptor (hPXR). In contrast, irinotecan was found to be an hPXR agonist in the same tests. CPT disrupted the interaction of hPXR with steroid receptor coactivator-1 (SRC-1) but had no effects on the formation of the hPXR and retinoid X receptor α (RXRα) heterodimer. Nor had it effects on the interactions between the regulatory complex and DNA responsive elements. CPT treatment resulted in delayed metabolism of nifedipine induced by rifampicin in human hepatocytes, suggesting a potential drug-drug interaction (DDI) between CPT and CYP3A4 metabolized drugs. The study found a novel potent hPXR antagonist and indicated the potential of a new class of compounds to control drug efficacies in cancer therapy.
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 2667.
Abstract 2671: Structural analysis of the inhibitory mechanism of AP24534, a pan-BCR-ABL inhibitor overriding the T315I gatekeeper mutation
Authors: Zhu Xiaotian , Zhou Tianjun , Shakespeare William C. , Huang Wei-Sheng , Commodore Lois , Metcalf Chester A. , Wang Yihan , Thomas Mathew , Sundaramoorthi Raji , Zou Dong , Sawyer Tomi K. , Clackson Tim , Dalgarno David C. 
Published: February 2011

Abstract
Although durable response in many chronic myeloid leukemia (CML) patients can be achieved by imatinib treatment, point mutations in the kinase domain of the BCR-ABL fusion protein can lead to drug resistance and relapse. Nilotinib and dasatinib, the two second generation Abl kinase inhibitors, are active against most imatinib resistant mutants with a few exceptions, particularly the T315I gatekeeper residue mutation. Using a structure-based approach we have identified AP24534, a molecule that potently inhibits the T315I mutant and all other mutants tested, thus acting as a pan-BCR-ABL inhibitor. To elucidate the basis for this unique profile of AP24534, we have used a combination of X-ray crystallographic and structure-activity relationship analysis on AP24534 and its analogs. The crystal structure of the T315I mutant Abl in complex with the inhibitor clearly demonstrates that AP24534 binds to Abl in a DFG-out binding mode with the ethynyl chemical moiety skirting the mutated gate-keeper residue avoiding steric clashes. The X-ray co-structures of both the wild type and the T315I mutant Abl, in conjunction with the SAR analysis, further reveal that AP24534 retains potency against the T315I and other imatinib-resistant ABL mutants through optimized multiple points of contact, balancing and distributing the overall binding affinity so that mutation-based disruption of one facet of the binding network results in only a slight reduction in binding affinity. Our structural analysis enables us to predict and rationalize the different degree of sensitivity of ABL point mutants to AP24534, and to understand how AP24534 can completely abrogate resistance in cell-based mutagenesis screens at relatively low concentrations. AP24534 is currently being investigated in a Phase I clinical trial in patients with refractory and resistant CML and other hematological malignancies.
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 2671.
Abstract 2674: Interaction of natural alkaloids with G-quadruplex structures: biophysical and pharmacological implications
Authors: Bianco Sara , Bazzicalupi Carla , Gratteri Paola , Bilia A. R. , Schwalbe H. , Richter C. , Palumbo Manlio , Sissi Claudia 
Published: February 2011

Abstract
DNA sequences rich in guanines can fold up to form peculiar structures, known as a G-quadruplex, deriving from pairing of four guanines by Hoogsteen-like hydrogen bonds. Nowadays, these structure(s) are being exploited as suitable targets for anti-cancer drug design. Indeed, G-quadruplexes can be formed at the telomers, the ends of human chromosomes as well as in the promoters of several important oncogenes such as c-myc, bcl-2, c-kit and VEGF. At physiological conditions an equilibrium between different conformations builds up. It has been shown that the interconversion between folded-unfolded conformation can be used by the cell to modulate the oncogene transcriptional state. Up-to-date, several classes of compounds have been tested and identified as efficient G-quadruplex binders. DNA recognition occurs mainly through stacking on a terminal G-tetrad, thus, these ligands share a general consensus structural motif based on a large flat aromatic surface. Several natural compounds characterized by cytotoxic activity present this structural motif. Here, we selected several structurally related natural derivatives of plant origin characterized by four fused rings with different degree of π electron delocalization. Among them, Berberine, Sanguinarine and Cheleritrine were identified as the most efficient stabilizers for G-quadruplex structures. Their interaction with various nucleic acid conformations was examined in detail in terms of affinity constant and mode of binding by NMR studies, spectroscopic (fluorometric and CD) and ITC titrations. In particular, we focussed our attention on the role of DNA sequence and structure on binding geometry and affinity. Biophysical data were then related to the cytotoxic response of each derivative. From these data we could asses the potential of the tested ligands as G-quadruplex binders (and prospective drug response) at physiological conditions.
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 2674.
Abstract 268: Regulation and function of ERBB3 signaling pathway in clear cell sarcoma
Authors: Zhang Yixiang , Davis Ian J. , Remillard Stephen P. , Demetri George D. , Fisher David E. , Wagner Andrew J. 
Published: February 2011

Abstract
Clear Cell Sarcoma (CCS), a soft tissue malignancy of tendons and aponeuroses in children and young adults, is notoriously resistant to radiation and chemotherapy, and new approaches to treatment are needed. We recently demonstrated the involvement of the MET receptor tyrosine kinase (RTK) in regulation of the growth, migration, and invasion of CCS cells. However, pharmacologic agents targeting the HGF:MET axis could neither completely inhibit cell growth nor significantly induce apoptosis. To determine whether other RTKs might cooperate with MET in control of survival and proliferation of CCS cells, we used phospho-RTK arrays to assess the activation status of RTKs in three CCS cell lines (CCS292, DTC1, SU-CCS-1). We found that in addition to MET, ERBB3 was strongly activated in CCS. Western blot analysis confirmed constitutive activation of ERBB3 in CCS292 and DTC-1 cell lines and expression in all three lines. Since ERBB3 lacks intrinsic kinase activity, we searched for potential heterodimerization partners. Interestingly, we found that the activation of ERBB3 in different CCS cell lines relied on different partners: ERBB2 as a pivotal partner in CCS292, and MET as a pivotal partner in DTC-1. Moreover, we explored the possibility of a linkage between the CCS pathognomonic EWS-ATF1 fusion product and ERBB3 activation. We found that EWS-ATF1 knockdown resulted in both decreased expression of the ERBB3 ligand Neuregulin 1 and less ERBB3 phosphorylation in CCS292 cells, but had no effects on ERBB3 phosphorylation in DTC-1 cells. To explore the biological function of ERBB3, we applied siRNA or small molecule inhibitors of RTKs to CCS cell lines and determined the biological consequences by cell viability, cell cycle and apoptosis assays; these studies show that ERBB3 in conjunction with MET played an important regulatory role in the proliferation and survival of CCS cells. These data suggest that combined inhibition of the MET and EGFR signaling pathways may be a rationally designed strategy for treatment of patients with advanced CCS.
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 268.
Abstract 2682: Integration of multiple prognostic factors into the TNM staging system using a new algorithm that censors patients
Authors: Henson Donald , Chen Dechang , Schwartz Arnold , Hart Alexandra , Pham Ly , Hsiao Joyce , Cheng Xiuzhen 
Published: February 2011

Abstract
Objective: To integrate new and baseline multiple prognostic factors into the TNM (Tumor, Lymph Node, Metastasis) cancer patient staging system using a new cluster algorithm that is able to censor patients.
Methods: Records of women with invasive breast cancer from 1990-2000 were obtained from NCI's Surveillance, Epidemiology, and End Results (SEER) Program. The dataset contained 140,714 patients. Cancer specific survival rates for 60 and 120 months and hazard rates were calculated by the Kaplan-Meier method for all combinations tumor size, lymph node status, histological grade, and estrogen receptor status. The algorithm stratified (clustered) patients according to survival based on prognostic factors. The algorithm uses partitioning and hierarchical categorization. The partitioning step involves repeated use of the algorithm Partition Around Mediods to partition combinations in terms of their survival differences. Survival rates were compared by the logrank test.
Results: From the 140,714 patients, survival and hazard rates were calculated for each combination of the 4 prognostic factors using survival rates for partitioning. Each combination formed a cluster, 96 with 4 factors. In all cases, there was a relation between the prognostic factors and the outcome. The histological grade, tumor size, number of positive lymph nodes, estrogen receptor status all had an effect on survival, which is recognized from clinical experience. Any number of additional factors can be included.
Conclusions: The clinical application of this new clustering algorithm is practical and can be applied to host and tumor factors. The algorithm calculated survival and hazard for all combinations of 4 major prognostic factors for breast cancer. This is the first cluster algorithm that is able to censor patients and overcome the limitations of the TNM bin model.
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 2682.
Abstract 2686: Analysis of cardiac markers on patients receiving 5-fluorouracil, epirubicin, cyclophosphamide with concurrent celecoxib (FEC-C) neoadjuvant therapy for locally advanced breast cancer
Authors: Yip Adrian Y.S , Loo Wings T. , Chow Louis W.C. 
Published: February 2011

Abstract
INTRODUCTION/PURPOSE: Anthracycline is widely used and studied in neoadjuvant setting for treatment of locally advanced breast cancer (LABC) for many years. Addition of Cyclooxygenase-2 (COX-2) inhibitors might potentiate the anti-cancer effect of chemotherapy and yet, in consideration of its possible cardiotoxicity, many studies were halted. This sub-study is to evaluate the change in serums level of cardiac troponin I (cTnI), N-Terminal Pro B-Type Natriuretic Peptide (Nt-proBNP) and lactate dehydrogenase (LDH) in LABC patients treated with FEC-C.
METHODS: A study group of 34 patients, who received three cycles of neoadjuvant FEC every 3 weeks with concurrent oral celecoxib (F: 500mg/m2; E: 75mg/m2; C: 500mg/m2; Celecoxib: 400mg bid), were included in the cardiac marker analyses. Marker levels of cTnI, Nt-proBNP and LDH in serum samples before treatment and after each cycle of therapy were studied.
RESULTS: Patients tolerated well with this regimen. Neither life-threatening toxicity nor clinical symptom of cardiac damage was observed. Across the three time-points of assessments, the mean cTnI did not exceed the upper limit of normal of 0.2 ng/ml, albeit subtle fluctuation in some patients most likely due to anthracycline-based chemotherapy. After 3 cycles of FEC, the mean cTnI was measured 0.06 ng/ml. Nt-proBNP markers did not change significantly during chemotherapy and the means were less than 250 fmol/ml. Serum LDH, a less specific marker, increased from baseline after 3 cycles of FEC-C insignificantly (p = 0.181) while its changes across treatments were within the normal range of 313 – 618 U/L.
CONLCUSIONS: Neoadjuvant FEC-C therapy is an active and well tolerated regimen. The short-term use of anthracycline-based chemotherapy with COX-2 inhibitor for LABC before operation incurred some changes on cardiac markers. The change however did not outrange the normal values and indicate any cardiac damage.
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 2686.
Abstract 2707: Impact of accuracy in O6-methylguanine-DNA methyltransferase methylation assays for temozolomide efficacy on glioblastoma
Authors: Nagane Motoo , Kobayashi Keiichi , Shimizu Saki , Shiokawa Yoshiaki , Waha Andreas 
Published: February 2011

Abstract
Background: O6-methylguanine-DNA methyltransferase (MGMT) is implicated in resistance to temozolomide (TMZ). MGMT status has been shown to correlate with survival of patients with glioblastoma (GBM). We evaluated the relationship between promoter methylation status and protein expression of the MGMT gene in patients with GBM treated with TMZ, and also analyzed their prognostic value regarding response to TMZ and survival.
Methods: We analyzed 47 GBM tissues from 43 patients treated with TMZ from September 2003 to January 2009. Among them, 22 patients with recurrent GBM treated with standard TMZ single therapy were subjected to survival analyses. TMZ was given daily orally 75mg/m2 during radiotherapy, or as standard 5/28-day regimen. MGMT protein expression was quantified by Western blotting, and promoter methylation status was determined by both methylation-specific PCR (MSP) and quantitative pyrosequencing.
Results: MGMT promoter methylation was detected in 19/47 cases (40.4%) by MSP, 16/47 (34%) by pyrosequencing, and was significantly correlated with each other (p&lt;0.001). The methylation status correlated significantly with MGMT protein expression as well. Upon TMZ treatment for recurrent GBM, patients with both methylated MGMT promoter by MSP and low MGMT protein expression had a significantly improved progression-free survival (PFS) and overall survival (OS), whereas methylation status by pyrosequencing data did not. MGMT status was the only significant prognostic factor for PFS and OS.
Conclusions: The three MGMT assays revealed similar methylation/expression patterns and were suggested to be important prognostic factors for patients treated with TMZ. Whether precise quantification of the methylation status provides any clinically relevant information on the treatment strategy for GBM needs to be further investigated.
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 2707.