bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3499: Nanoparticle formulation of SN-38 by the IVECT method results in a safer, more effective treatment for colorectal cancer
Authors: Carie Adam E. , Rios-Doria Jonathan , Cardoen Gregoire , Costich Tara Lee , Sill Kevin 
Published: February 2011

Abstract
Polymeric micelles represent an emerging class of nano-scale vehicles with unmatched potential for delivering potent, targeted chemotherapy. Intezyne's advanced tri-block copolymer system, the IVECT(TM) Method, has been proven to encapsulate a wide variety of therapeutic and diagnostic agents into a proprietary micelle with unique physiochemical properties. Conventional micelles become destabilized rapidly upon dilution into the bloodstream and release a significant portion of their drug payload systemically, harming healthy tissues and limiting therapeutic effects. Intezyne's IVECT Method utilizes a unique cross-linked stabilizer block that maintains micellar structure for a longer period of time post administration and is designed such that a downshift in pH at the tumor activates drug release by destroying the zinc cross-link, allowing for focused drug exposure. The IVECT Method's unmatched plasma stability allows for longer circulation times while protecting healthy tissues, and it maximizes tumor retention and efficacy through the enhanced permeability and retention (EPR) effect and pH-responsive cross-linker. Intezyne's lead product IT-141 encapsulates the extremely potent active metabolite of irinotecan, SN-38. Recently, IT-141 has demonstrated 14-fold greater plasma exposure and 8-fold greater tumor accumulation vs. irinotecan. This superior pharmacokinetic profile confers 500% greater anti-tumor activity at half the dose (30mg/kg, 3X Q4D, vs. 60mg/kg irinotecan). In xenograft models, IT-141 has demonstrated tumor regression of up to 88%, with 60% of tumors regressing completely. The IVECT copolymer is safe and well tolerated at up to 6 times the therapeutic doses, with no sick mouse syndrome, and can be lyophilized for long-term storage (&gt;1 year). Intezyne is preparing its IND for IT-141. The Company has additional programs in development that focus on delivering best-in-class chemotherapies.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3499.
Abstract 3509: Design, synthesis and biological evaluation of a novel series of anthrapyrazoles linked with netropsin-like oligopyrrole carboxamides as anticancer agents
Authors: Zhang Rui , Wu Xing , Guziec Lynn , Guziec Frank , Yalowich Jack C. , Chee Gaik-Lean , Hasinoff Brian B. 
Published: February 2011

Abstract
Anticancer drugs that bind to DNA and inhibit DNA-processing enzymes represent an important class of anticancer drugs. Combilexin molecules, which combine DNA minor groove binder and intercalator functionalities, have the potential for increased DNA binding affinity and increased cytotoxicity due to their dual mode of DNA binding. In this study DNA minor groove binder netropsin analogs containing either a mono-N-methylpyrrole carboxamide or two units of N-methylpyrrole carboxamide linked to DNA intercalating anthrapyrazoles were synthesized. Two of the hybrid molecules which possessed bis-methylpyrrole moities and amine head groups displayed submicromolar cytotoxicity towards K562 human leukemia cells. The synthesized hybrids were also evaluated for DNA binding by measuring the increase in DNA melting temperature, for DNA topoisomerase IIα-mediated double strand cleavage of DNA, for inhibition of DNA topoisomerase IIα decatenation activity, and for inhibition DNA topoisomerase I relaxation of DNA. Several of the compounds stabilized the DNA-topoisomerase IIα covalent complex, indicating that they acted as topoisomerase IIα poisons. The results indicate that the hybrid agents have higher affinity for DNA than the parent compounds. In conclusion, a novel group of compounds combining DNA intercalating anthrapyrazoles and minor groove binding netropsin analogs have been designed, synthesized and biologically evaluated as possible novel anticancer agents. Support: CIHR, a Canada Research Chair in Drug Development, National Institutes of Health grant CA090787 to J.C.Y., the Dishman Foundation at Southwestern University and the Robert A. Welsh Foundation.
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 3509.
Abstract 3511: Modulation of HIF-1α by topotecan is related to topoisomerase I-associated with HIF-1α mRNA in ovarian cancer
Authors: Parmakhtiar Basmina , Han Ernest , Fruehauf John P. 
Published: February 2011

Abstract
Topotecan (TPT) is an agent which targets topoisomerase I (Topo I) and is used in the treatment of platinum-resistant and/or recurrent ovarian cancer. We have previously reported that topotecan inhibits hypoxia inducible factor 1α (HIF1α) stabilization, leading to decreased HIF-1α protein and depression of vascular endothelial growth factor (VEGF) levels in ovarian cancer cell lines. Furthermore, we have shown a Topo I: HIF-1α mRNA association using RNA-immunoprecipitation. The aim of this study was to further elucidate the mechanism by which topotecan knocks down HIF-1 alpha and the nature of its dependence on Topoisomerase I. CAOV3 (high Topo I expressing) ovarian cancer cells were used to carry out Topo I knockdown studies using Topo I siRNA in both normoxic and hypoxic (0.5% O2) conditions. Topo I and HIF-1α transcript levels were determined by quantitative PCR and protein expression was evaluated via western blot analysis. Topo I and HIF-1α protein levels were normalized to B-Actin controls. RT-PCR analysis did not show a significant decrease in HIF-1α transcript levels with Topo I siRNA treatment compared to untreated and negative control siRNA treated cells. An 80% decrease in Topo I protein expression was obtained using 30nM Topo I siRNA for both normoxic and hypoxic conditions. An ∼2.30 fold increase in HIF-1α protein expression was seen in Topo I knockdown cells compared to negative control siRNA treated cells after 800nM topotecan treatment under hypoxic conditions. 800nM TPT yielded an 80% decrease in Topo I protein expression with negative control siRNA treated cells under both normoxic and hypoxic conditions. However, 800nM TPT showed complete inhibition of Topo I protein stabilization in Topo I siRNA treated cells. Our results suggest that Topo I is required for Topotecan to inhibit HIF-1α protein stabilization. Furthermore, they also suggest that Topo I may be modulating its own transcript levels. Further studies are being carried out to verify these findings and will be reported at the AACR conference.
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 3511.
Abstract 3512: Novel DNA alkylating agent BO-1090 is a potential candidate for oral cavity cancer therapy
Authors: Sanjiv Kumar , Su Tsann-Long , Lee Te-Chang 
Published: February 2011

Abstract
Human death from oral cancer is the 4th most common in male and over all 6th most common cause of cancer death in Taiwan. Surgery, radiotherapy in combination with chemotherapy is the most common line of treatment for oral cavity cancer. Although cisplain, 5FU, Docetexal, Pinyangmycin etc are the common drugs being used in clinic, there is no any specific drug for oral cavity cancer. In that direction BO-1090 a newly synthesized alkylating agent has potential to be more specific drug for oral cancer based on its potent in vitro cytotoxicty to oral cancer cells, such are OECM-1, SAS, OC3 and CAL-27 in comparison to other cancer cell lines, including lung cancer H1299, prostate cancer cell PC3 and neuronal cell line U87. BO-1090 target DNA for its cytotoxic effects that have been confirmed by alkaline gel shift assay, BrdU based DNA synthesis inhibition assay, Comet assay and γH2x detection. BO-1090 has been tested for its therapeutic potential in SAS cell xenograft mouse. At a dose of 60 mg/Kg i.v five times, it significantly delays the tumor growth in comparison to the control group of mice. Its tumor efficacy in SAS cell xenograft is better than the cisplatin at dose of 4 mg/kg i.v three times. Based on these preliminary results it suggests that B0-1090 can be a useful drug either alone or in combination with other knows drugs in oral cavity cancer therapy. As to the modes of actions of BO-1090, here is activation of CHK-2 check point in response to DNA damage by BO-1090 as well as late activation of p53 and p21. The late activation of P53 may be due to DNA replication blocked by BO1090. During propidium iodide staining based cell cycle analysis, BO-1090 induces G1/ S phase arrest in SAS cell that further confirmed by BrdU incorporation based pulse chase experiment. G1/S phase arrest may be due to combined effects of CDC 25A degradation and activation of p53 and p21 in response to BO-1090 induced DNA damage. G1/S phase arrest in cell by BO-1090 is not a common feature of a DNA alkylating agent, most of DNA alkylating agent induce G2/M phase arrest. In Annexin V based apoptosis assay, our results show that BO-1090 induces apoptosis in SAS and OECM-1 cell by time and dose dependent manner through caspase dependent pathway. By using bioinformatic approach and preliminary experiments suggest that PIM-1 may be also one of its molecular targets.
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 3512.
Abstract 3528: Mutational analysis of threonine 402 adjacent to the GXXXG dimerization motif in TM1 of ABCG2
Authors: Ierano Caterina , Polgar Orsolya , Tamaki Akina , Stanley Bradford , Ward Yvona , Xia Di , Tarasova Nadya , Robey Robert W. , Bates Susan E, 
Published: February 2011

Abstract
ABCG2 is an ATP-binding cassette half-transporter important in normal tissue protection, drug distribution and excretion. ABCG2 requires homodimerization for function, though the mechanism for dimerization has not been worked out. We carried out mutational analysis of threonine 402, three residues away from the GXXXG motif in TM1, to study its potential role in ABCG2 dimerization (TXXXGXXXG). Single mutations to leucine (T402L) or arginine (T402R) did not have significant impact on the ABCG2 protein. On the other hand, combining the T402 mutations with the GXXXG glycine to leucine mutations (T402L/G406L/G410L and T402R/G406L/G410L) resulted in substantially reduced expression, altered glycosylation, degradation by a proteosome independent pathway and partial retention in the endoplasmic reticulum as suggested by immunostaining, Endoglycosidase H sensitivity and MG132 and bafilomycin failed effect. The T402L/G406L/G410L mutant when incubated with the ABCG2-substrate mitoxantrone showed a shift on immunoblot analysis to the band representing the fully matured glycoprotein. The T402R/G406L/G410L mutant carrying the more drastic substitution failed to shift to the surface with mitoxantrone. The same set of mutations also displayed impaired dimerization in the TOXCAT assay for TM1 compared to the wild type. Homology modeling of ABCG2 places the TXXXGXXXG motif at the dimer interface. These studies are consistent with a role for the extended TXXXGXXXG motif in ABCG2 folding, processing, and/or dimerization.
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 3528.
Abstract 3531: Different isoforms of drug-resistant genes may influence breast cancer survival
Authors: Elshimali Yayha , Chen Daniel , Wu Yanyuan , Vadgama Jaydutt V. 
Published: February 2011

Abstract
One major impediment to the success of chemotherapy in cancer patients is the risk of developing drug resistance. One mechanism leading to multidrug resistance in cancer therapy is through the ABC transporters. The eukaryotic ABC genes are organized as transporters containing two transmembrane and two ATP binding domains. Alternative splicing is one major mechanism in which a single gene generates functional diversity by producing different spliced isoforms. To determine the variability of ABC transporters, we performed exhaustive search of the NCBI database for ABC transporter genes, in addition to using the Alternative Splicing Annotation Project (ASAP) and the Alternative Splicing Database (ASD). We conducted immunostaining for MRP1 and MDR1 on tissue micro array of 23 breast cancer patients and RNA mediated annealing, selection, extension and ligation (RASL) assay for analysis of mRNA splicing isoforms which was performed on exon/exon target. Tumor cells from chemotherapy resistant patients show specific expression patterns of drug-resistant ATP-binding cassette transporter. Our data showed alternative splicing in 3 and 4 exon/exon borders in MDR1 and PGP genes. Two splicing events in MDR1 and one in PGP transcripts were predicted to be alternatively spliced in ASAP database. Interestingly, exon11/12 border in MDR1 is found to be alternatively spliced. In summary, protein microarray analysis demonstrated significant correlation between MRP1 expression and survival rate within 5 years. In contrast, MDRI protein expression did not correlate with 5 year survival rate. This may be due to variations in the MDR1 isoforms.
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 3531.
Abstract 3533: Resistance is useless: Development of the MDR1-selective agent NSC73306
Authors: Hall Matthew D. , Handley Misty D. , Pluchino Kristen , Brimacombe Kyle R. , Gottesman Michael M. 
Published: February 2011

Abstract
The thiosemicarbazone NSC73306 is one of several agents identified in a screen for agents that selectively kill cells expressing the multidrug resistance transporter P-glycoprotein (MDR1, ABCB1, P-gp). Prolonged exposure of P-gp expressing cells to NSC73306 down-regulates P-gp, re-sensitizing the cells to conventional chemotherapeutics. Given the exciting potential for NSC73306 as a potential therapy for previously intractable multidrug resistant cancer cells, in vitro and in vivo validation is underway. A series of NSC73306 analogs have been synthesized in order to examine the structural requirements for MDR1-selectivity of this family of compounds, and a proposed pharmacophore for MDR1-selectivity has been generated. In parallel, new MDR1-selective chemotypes are being discovered and validated through a number of strategies, including bioinformatic, high throughput screening and drug design approaches.
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 3533.
Abstract 3536: The biphasic mechanism of TNF-alpha mediated modulation of mdr1 expression and chemosensitization of colon cancer cells is linked to the NFkappaB pathway
Authors: Walther Wolfgang , Bauer Lisa , Aumann Jutta , Stein Ulrike 
Published: February 2011

Abstract
Multidrug resistance (MDR) is one major cause for cancer chemotherapy failure. Therefore, numerous overcoming strategies have been tested for tumor chemosensitization. Among these, persistent action of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF) showed great potential for downregulation of MDR-associated genes, particularly for the ABC-transporter P-glycoprotein Pgp, encoded by the mdr1 gene. These cytokine-mediated effects are still under controversial discussion, since transient action of TNF was shown to increase mdr1 expression, whereas persistent TNF action reduces mdr1 expression. Key mediator for this is the transcription factor NFkappaB/p65. This factor is acting via binding to NFkappaB/p65 consensus sequences within the mdr1 promoter. To determine the cellular mechanisms of TNF mediated modulation of mdr1 expression, we analyzed transient and persistent effects in regard to biphasic NFkappaB signaling in colon carcinoma cells.
The mdr1 overexpressing, multidrug resistant human HCT15 colon carcinoma cells were treated for transient 30 to 120 min or long-term, 24 to 96 h incubations with TNF. The TNF mediated modulation of mdr1 expression was analyzed by real-time RT-PCR and Western-blot. Involvement of TNF-receptor I or II and time-dependent analysis of NFkappaB/p65 signaling was determined by Western blot, luciferase cell signaling reporter assay and EMSA.
Our studies revealed that the persistent long-term action of TNF leads to down-regulation of mdr1 at mRNA and protein level. We showed, that this effect is mediated by TNF-receptor I, which is known to trigger the NFkappaB/p65 pathway. More importantly, the persistent TNF action on the colon cancer cells abolishes TNF mediated induction of the NFkappaB/p65 signaling, associated with reduced nuclear accumulation of NFkappaB/p65 and also its impaired binding to the consensus sequence of the mdr1 promoter. This study supports the biphasic nature of TNF action and points to the contrary effects of transient or persistent action of this cytokine. It provides insights into mechanism of MDR overcoming in colon cancer and potential clues for effects associated with chronic inflammation of the intestine
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 3536.
Abstract 3543: Activation of the ERK pathways overcome the cisplatin-resistance in ovarian carcinoma cells
Authors: Nonaka Michiko , Itamochi Hiroaki , Kawaguchi Wakae , Uegaki Kazunori , Naniwa Jun , Sato Shinya , Shimada Muneaki , Oishi Tetsuro , Terakawa Naoki , Kigawa Junzo , Harada Tasuku 
Published: February 2011

Abstract
Objective: Cisplatin (CDDP) is a key drug used to treat ovarian carcinoma that activates the mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) signaling cascade and a phosphatidylinositol 3′-kinase (PI3K)-Akt pathway, both of which are considered pathways for cell proliferation and survival. The present study aimed to elucidate the roles of the MEK-ERK and PI3K-Akt pathways in regulating cytotoxicity in ovarian carcinoma cells induced by CDDP.
Methods: Seven human ovarian serous adenocarcinoma cell lines were used in this study (KF, KFr, KOC-2S, SK-OV-3, SHIN-3, TU-OS-3, and TU-OS-4). We treated the cell lines with CDDP combined with PI3K inhibitor (LY294002 [LY]), MEK inhibitor (PD98059 [PD]), or ERK activator (phorbol 12-myristate 13-acetate [PMA]), then assessed cell viability by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The levels at which proteins expressed MEK, phosphorylated (p)MEK, ERK, pERK, Akt, pAkt, and cleaved caspase-9 were detected by western blotting. Cell cycle distribution and apoptotic cells were determined by flow cytometry, 5-bromo-2-deoxyuridine (BrdU) incorporation, and staining with Annexin V.
Results: The range of IC50 to CDDP was 2.4 to 26.9 μM for those cell lines. KFr, a CDDP-resistant cell line, was established from KF cells, and the IC50 to CDDP was 9.6 μM. We defined the cell lines which had 9.6 μM or higher IC50 value as CDDP-resistance. Proteins MEK, pMEK, Akt, pAkt, ERK and pERK were expressed in all cell lines. CDDP combined with LY had an additive effect on inhibiting growth of cells in all lines. In contrast, we observed an antagonism for all cell lines when CDDP was combined with PD. Interestingly, growth of cells was dramatically suppressed when CDDP was combined with PMA in the CDDP-resistant cells (KFr, SK-OV-3, SHIN-3, TU-OS-3, TU-OS-4). Treatment with PMA upregulated protein expression levels of pERK and cleaved caspase-9 only in the CDDP-resistant cells. CDDP combined with PMA increased the S-phase fraction and apoptotic cells in the CDDP-resistant cells. Conclusion: ERK activated by PMA may overcome resistance to CDDP in ovarian carcinoma cells.
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 3543.
Abstract 3551: Role of proteasome in the development of multidrug resistance in childhood rhabdomyosarcoma
Authors: Armeanu Sorin , Laizer Natalie , Brücher Björn , Fuchs Jörg , Seitz Guido 
Published: February 2011

Abstract
Multidrug resistance (MDR) is a common problem in the treatment of childhood rhabdomyosarcoma (RMS). The aim of this study was to investigate different mechanism of MDR in childhood RMS and to analyze possible reversal strategies.
Female athymic mice underwent xenotransplantation with embryonal (A204) or alveolar (Rh30) RMS cells and were treated with vincristine (0.75 mg/kg/d i.p.). Gene expression analysis with Affymetrix oligonucleotide microarrays HU-Gene 1.0 revealed 2314 differentially expressed genes between the groups in alveolar RMS and 1387 in embryonal RMS. Ingenuity Pathways Analysis of biological pathways and functions of these genes revealed a cluster 21 genes related to the ubiquitin pathway. Among them 4 genes shown an up-regulation and 17 a 0.5 lower expression in vincristine treated samples. Furthermore, among of 45 genes of the proteasome cluster with 35 being down-regulated in RMS from animals treated with vincristine, putative mediating the development of MDR. Changes of gene expression were confirmed by qRT-PCR for selected proteasome components, such as PSMB1, PSMB6 and PSMD14. Specific inhibition of proteasome activity with bortezomib and MG132 inhibits proliferation of RMS cells, but reduces the cytotoxic activity of vincristine in a cell vitality assay. Our results emphasize the role of proteasome in the development of MDR in rhabdomyosarcoma treated with vincristine.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3551.