bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1306: A Phase 1b/2a study of CRLX101, a novel nanopharmaceutical of camptothecin, in solid tumor cancer patients who have failed standard therapy
Authors: Weiss Glen , Yen Yun , Neidhart Jeffrey , Young Cissy S. , Weiss Sara , Ryan John 
Published: June 2012

Abstract
Results from a 24-patient dose-escalation safety and tolerability Phase 1 study of CRLX101 were presented at the 22nd EORTC-NCI-AACR symposium in November 2010. A Phase 2a expansion study of CRLX101 has been initiated to investigate the biological activity and tolerability in cancer patients with specific tumor types at the maximum-tolerated dose (MTD) of 15 mg/m2. Specifically, a focus of the Phase 2a expansion study is to evaluate CRLX101 biological activity in non-small cell lung carcinoma (NSCLC), amongst other target indications.
In this Phase 2a expansion study, thirty-six (36) patients will be enrolled from three (3) clinical sites in the United States. Fifteen (15) patients treated with CRLX101 thus far were patients with advanced NSCLC. Stable disease of greater than 6 months in multiple NSCLC patients treated with CRLX101 has been observed. Dose-limiting bone marrow toxicities of thrombocytopenia and neutropenia were addressed with the longer dosing interval of an every-other-week dosing schedule, which accommodates for the prolonged half-life of CRLX101. Hemorrhagic cystitis, the classic camptothecin toxicity, has not been observed. No other significant adverse events have been observed in the current study.
The Phase 2a study will be fully enrolled by the end of 2010 with extensive follow-up on most patients by April of 2011. All of the safety, tolerability, and biological activity data will be presented. At this time, twenty-one (21) of the thirty-six (36) patients have been enrolled. To date, three (3) NSCLC patients have received 4 cycles of therapy and are continuing on study. One (1) NSCLC patients is receiving the seventh cycle of therapy.
A controlled, randomized Phase 2 study of CRLX101 in NSCLC is planned and will be initiated in early 2011. CRLX101's favorable tolerability profile may enable combination therapy with other cytotoxic drugs including carboplatin and gemcitabine without added toxicities. Preclinical data on the efficacy and tolerability of such combinations will also be presented. In addition, the dual activity of CRLX101 against both topoisomerase-1 and HIF1α suggest that combination with VEGF antagonists could be synergistic. Similarly, pre-clinical data on the dual mechanism inhibition by CRLX101 based on its pharmacokinetics will be presented.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1306. doi:10.1158/1538-7445.AM2011-1306
Abstract 1322: Molecular mechanisms of high glucose-induced toxicity in human breast adenocarcinoma (Mcf-7) cells
Authors: Yedjou Clement G. , Tchounwou Christine K. , Tchounwou Paul B. 
Published: June 2012

Abstract
Glucose is a simple sugar that your body relies on it to produce energy. It has been shown that high glucose is related to many long-term health problems including the kidneys, nerves, eyes and vision, risk of heart disease and stroke, erectile dysfunction in men and pregnancy complications in women. Epidemiological data have suggested an increased cancer rates in diabetic patients, for which the underlying mechanism is poorly understood. Hence, the aim of the present investigation was to evaluate the cell viability of human breast adenocarcinoma (MCF-7) cells exposed to different doses (0, 5, 10, 20, 40, 80 mg/mL) of D-glucose by the means of trypan blue exclusion test and MTT assay, respectively. The degree of DNA damage and early stage apoptosis were also tested by the means of alkaline single cell gel electrophoresis (Comet) assay, and flow cytometric analysis using Annexin V FITC/PI. The results of MTT assay indicated that low dose (5 mg/mL) of D-glucose slightly increase cell viability upon 2 h of exposure. On the other hand, high doses (10-80 mg/mL) of D-glucose significantly reduce the viability of MCF-7 cells in a dose and time-dependent manner. Similar trend was obtained with the trypan blue exclusion test. Data obtained from the comet assay indicated that D-glucose causes DNA damage in MCF-7 cells in a dose-dependent manner. The flow cytometric assessment (Annexin V FITC/PI) showed a strong dose-response relationship between high glucose exposure and annexin V positive cells undergoing early stage apoptosis in MCF-7 cells. Based on these direct in vitro findings, our study shows clear evidence that elevated level of D-glucose induced cytotoxic and genotoxic effects, and apoptosis in MCF-7 cells. This finding provides evidence that elevated level of glucose may be is associated with diabetic complications in vascular endothelium of the female breasts.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1322. doi:10.1158/1538-7445.AM2011-1322
Abstract 1332: Cigarette smoking attenuates TGF-β-mediated tumor suppression function through down-regulation of Smad3 in lung cancer
Authors: Samanta Debangshu , Gonzalez Adriana , Datta Pran K. 
Published: June 2012

Abstract
Cigarette smoking has been connected to an array of chronic lung diseases and one of the major causes of morbidity and mortality. Epidemiological studies have demonstrated the most cases of lung cancers (85-90%) are directly attributable to tobacco smoking. Although much information is gained about the effect of cigarette smoking on various signaling pathways causing lung cancer, no information is available about the effect cigarette smoking on the TGF-β-dependent initiation and progression of lung cancer. To address this issue, A549, a lung adenocarcinma cell line and HPL1A, an immortalized lung epithelial cell line were chronically treated with cigarette smoke condensate (CSC) to mimic the conditions of long-term cigarette smoking. Prolonged exposure of these cells to CSC resulted in a decrease in Smad3 and Smad4 complex formation and TGF-ß-mediated transcription due to reduced expression of Smad3. As a consequence, the cells were less apoptotic, were more viable, and lost TGF-β mediated growth inhibition. We found that the decrease in apoptosis is due to the up-regulation of Bcl2, which is a downstream target of Smad3. The repression of Smad3 expression is at the promoter level and is due to histone deacetylation. Withdrawal of CSC treatment resulted in the restoration of Smad3 expression, reduction in cell viability and increased TGF-β mediated growth inhibition. Rescue experiment with reintroduction of Smad3 in the 300 day CSC treated cells restored TGF-β signaling, increased apoptosis and decreased cell viability. Finally, three hundred days CSC exposure dramatically increased the tumorigenicity of cells in vivo, and Smad3 re-expression reverses this effect. In patient samples, there is a trend that expression of Smad3 goes down in smokers compared to non-smokers. Collectively, these data provide evidence that cigarette smoking promotes tumorigenicity partly by abrogating TGF-β mediated growth inhibition and apoptosis by reducing expression of Smad3.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1332. doi:10.1158/1538-7445.AM2011-1332
Abstract 1334: Benzo(a)pyrene concentration-dependent biotransformation and cytotoxicity in HT-29 colon cells
Authors: Myers Jeremy , Ramesh Aramandla 
Published: June 2012

Abstract
The majority of sporadic cancer deaths are attributed to environmental factors of which exposure to environmental toxicants is one. Benzo(a)pyrene (BaP), a member of the Polycyclic Aromatic Hydrocarbons (PAH) family of compounds is one such ubiquitous environmental toxicant; found in charcoal broiled/smoked meats, cigarette smoke, automobile exhaust, and industrial emissions. High levels of BaP have been detected in fat-rich foods such as dairy products, barbecued pork sausage, and beef meat. Since diet makes up a substantial amount of BaP intake (∼ 3 – 17 mg/person/day); ingested BaP contributing to gastrointestinal (GI) carcinogenesis deserves attention. Studies conducted using a mouse model in our laboratory has already shown that BaP contributes to colon cancer development. Through metabolic activation, BaP is biotransformed into an array of metabolites. Biotransformation of BaP proceeds through specific biochemical pathways (epoxide and quinone) each one producing specific reactive metabolites that bind with DNA, cause DNA damage and associated changes in cell cycle. The objective of this study was to determine the concentrations of BaP that are most toxic to HT-29 human colon cells and examine if any relationship exist between cellular toxicity and BaP biotransformation. Cells were cultured in Dulbecco's Modified Eagle Medium: Nutrient Mixture F-12 (DMEM/F12) supplemented with 10% FBS and antibiotics (penicillin/streptomycin). After revival of cells and growing them to confluence, cells were synchronized overnight by serum starvation method. The HT-29 cells were exposed to 1, 5, 10, 25, 50, and 100μM BaP over the course of 10 days and then counted using a Coulter Counter. Based on a concentration – response study 5, 10, and 25 μM BaP in DMSO (vehicle for BaP; 0.01%) were selected as optimal concentrations to analyze the effect of BaP on cell growth, viability, biochemical, and molecular endpoints 4 days after BaP exposure. The expression of both Phase I and II drug metabolizing enzymes were analyzed by western blot and RT-PCR. Analysis of cell cycle via FACS showed inhibition of the S and G2-phase in cells treated with increasing concentrations of BaP. An increase in CYP 1A1 and 1B1 expression also occurred in a BaP concentration-dependent manner. However, not much difference was seen in Phase II metabolizing enzyme expression levels regardless of the BaP concentrations tested. Our results suggest that BaP cytotoxicity is mediated by metabolic activation (funded by the NIH grants 5T32HL007735-12, 1RO1CA142845-01A1, 1S11ES014156-01A1 and Southern Regional Education Board).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1334. doi:10.1158/1538-7445.AM2011-1334
Abstract 1335: Phosphorylation of serine 9 is required for benzo(a)pyrene induced GNMT nuclear translocation
Authors: Lu Yao-Cheng , Yen Chia-Hung , Lai Xiu-Ting , Chen Yi-Ming A. 
Published: June 2012

Abstract
Glycine-N-methyltransferase (GNMT) is a protein with multiple functions. It can affect genetic stability by (1) regulating the ratio of S-adenosylmethionine to S-adenosylhomocystine and (2) binding to folate. In addition to act as a tumor suppressor for liver cancer, GNMT participated in the detoxification pathway by interacting with environmental carcinogens [such as benzo(a)pyrene (BaP), aflatoxin B1 (AFB1)] and decreasing subsequent DNA adducts formation and cytotoxicity. GNMT was primarily expressed in cytoplasm and partially translocated to cell nuclei after BaP treatment. Despite the mechanism of GNMT nuclear translocation remains unclear, it has been shown that the phosphorylation modification is important for GNMT nuclear translocation. The results from LC-MS/MS (liquid chromatography-tandem mass spectrometry) analysis showed that serine 9 of GNMT was phosphorylated after BaP treatment. The GNMTS9A mutant did not undergo nuclear translocation after BaP treatment by using indirect immunofluorescence assay. GNMT serine 9 was identified within an Akt1 consensus site by Scansite program. The co-immunoprecipitaion assay demonstrated that GNMT interacts with Akt. Akt phosphorylated GNMT only on serine 9 in vitro. Furthermore, BaP induced GNMT nuclear translocation was blocked by LY294002 treatment. In conclusion, the results suggested that the Serine 9, can be phosphorylated by Akt1, is an important phosphorylation site responsible for GNMT nuclear translocation after BaP treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1335. doi:10.1158/1538-7445.AM2011-1335
Abstract 1350: Novel ABI analogs target the colchicine site in tubulin and overcome multidrug resistance in metastatic melanoma
Authors: Li Wei , Chen Jianjun , Wang Zhao , Li Chien-Ming , Lu Yan , Dalton James T. , Miller Duane 
Published: June 2012

Abstract
With rapidly rising incidences of metastatic melanoma and its high resistance to current therapeutic agents, developing more effective drugs is urgently needed. We recently discovered a novel class of 2-aryl-4-benzoyl-imidazoles (ABI) analogs. These compounds showed great antiproliferative activity on melanoma cells and the IC50 is as low as 8 nM. ABIs showed equal potency against multidrug resistant melanoma cells and the sensitive parent cells, suggesting that they can effectively overcome P-gp meditated multidrug resistance. ABIs inhibited capillary network formation which indicates high potential for anti-angiogenesis. Cell cycle analysis showed ABIs arrested cells in the G2/M phase and inhibited tubulin polymerization. ABIs bind to the colchicine binding site in the α/β-tubulin heterodimer as indicated by a number of evidences including competitive binding and molecular modeling studies. Immunofluorescence experiments revealed that microtubule modality was dramatically changed with ABIs treatment. In vivo studies using both B16-F1/C57BL model and A375/SHO model showed significant inhibition of melanoma tumor growth by ABIs. These novel analogs hold great promise as new selective agents for the improved treatment of malignant melanoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1350. doi:10.1158/1538-7445.AM2011-1350
Abstract 1352: Mechanism of action of AL622, a molecule rationally designed to release an EGFR and a Src kinase inhibitor
Authors: Ning Na , Larroque-Lombard Anne-Laure , Huang Ying , Rao Suman , Jean-Claude Bertrand J. 
Published: June 2012

Abstract
In many solid tumors, including prostate and breast carcinomas, it has now been shown that Src synergizes with EGFR to promote cell proliferation and invasion. While molecules with EGFR and Src targeting functions have been designed, prodrugs capable of releasing optimized inhibitors of the two targets are scant. We designed AL622, which contains a quinazoline head targeted to EGFR and a hydrolysable linker that connects it to the PP2-like structure. HPLC analysis showed that this molecule is capable of releasing an EGFR inhibitor and intact PP2 inside the cells. The growth inhibition of AL622 in a panel of isogenic NIH3T3 cell lines (wt, Neu/ErbB2 and Her14/EGFR transfected) in comparison with Gefitinib (a clinically approved strong EGFR inhibitor) and PP2 (a Src-inhibitor) was assessed using the SRB assay. Like Gefitinib, AL622 blocked the proliferation of NIH3T3 cells transfected with the EGFR or Her2 gene. Although Gefitinib was twice as potent, AL622 showed a higher selectivity (fold selectivity = 1.77 for Neu-transfected and 1.63 for HER14-transfected cells). On the other hand, AL622 showed a 5-fold greater potency than PP2 in the EGFR and Her2 transfected cells. It was also much more selective than PP2 (fold selectivity = 35.9 for Neu-transfected and 37.8 for HER14-transfected cells). Western blot analysis in MDA-MB231 cells known to be characterized by Src-EGFR interaction showed that AL622 was capable of inducing a dose-dependent inhibition of EGFR and Src. In contrast, PP2 at an equidose was incapable of blocking EGFR but induced potent Src-inhibition. While Gefitinib induced some Src inhibition, it was less potent than AL622. Results from the wound healing assay showed that AL622 was capable of blocking the motility of 4T1 mouse breast cancer cells at doses comparable with those of PP2. However, a Boyden Chamber invasion assay showed that AL622 was capable of inducing more significant inhibition of invasion when compared with PP2 or the combination of PP2 and Gefitinib. The results in toto suggest that designing molecules to inhibit Src and EGFR can be an effective strategy to block aggressive proliferation and invasion in tumor cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1352. doi:10.1158/1538-7445.AM2011-1352
Abstract 1357: Inhibition of breast cancer cell growth by a synthetic ligand targeting the nuclear receptor, REV-ERB (NR1D1 and NR1D2)
Authors: Wang Yongjun , Kamenecka Theodore , Kojetin Douglas , Burris Thomas P. 
Published: June 2012

Abstract
Disruption of the circadian rhythm leads to increased risk for development of breast cancer in humans. The molecular mechanism underlying the link between circadian rhythm disruption and the increased risk of breast cancer in humans is not clear. The REV-ERBs are nuclear receptors that function as critical regulatory components of the circadian rhythm. We observed that REV-ERBbeta is highly overexpressed in multiple breast cancer cell lines, but not in the non-tumorigenic control breast cell line, MCF-10A. Furthermore, we show that a synthetic REV-ERB agonist that we discovered, SR9011, inhibits the proliferation of multiple breast cancer cell lines including triple negative breast cancers but has no effect on MCF10A cells. We discovered that the REV-ERBs directly regulates the expression of cyclin A2 gene suggesting a possible mechanism for inhibition of proliferation. Treatment of breast cancer cell lines with SR9011 repress the expression of cyclin A2 at both mRNA and protein levels. SR9011 treated SKBR3 cells display a reduced fraction of cells in S phase and in the G2/M phase. Administration SR9011 to synchronized SKBR3 cells results in about 8 hours delay of G2/M phase occurrence. Thus, our data suggests that REV-ERB is a valid target for development of anti-cancer agents and SR9011 holds promise for treatment of breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1357. doi:10.1158/1538-7445.AM2011-1357
Abstract 1359: Identification of a novel class of compounds as proteasome inhibitors: Synthesis and structure activity relationship studies of PI-1833 library
Authors: Ozcan Sevil , Aslamuzzaman Kazi , Marsilio Frank , Daniel Kenyon , Brooks Wesley , Guida Wayne , Lawrence Harshani , Sebti Said 
Published: June 2012

Abstract
The ATP-dependent ubiquitin-proteosome pathway is responsible for the controlled degradation of proteins in eukaryotic cells. The 26S proteosome is a multifunctional complex, consisting of a 19S regulatory particle (RP) and a 20S core particle (CP). The three main catalytic activities of the proteasome; peptidylglutamyl peptide hydrolysing (PGPH), trypsin-like (T-L), and chymotrypsin-like (CT-L), are mediated by three distinct catalytic β-1, β-2, and β-5 subunits, respectively. Owing to the central role of proteosome in maintaining homeostasis and hence its key position in many cellular processes, the development of inhibitors for CT-L activity has been the subject of considerable interest in the treatment of cancer. Selective inhibition of the CT-L activity of 20S proteasome represents a successful strategy in cancer therapy as demonstrated by Bortezomib (Velcade), a clinically approved drug for multiple myeloma and mantle lymphoma. Toxicity and tumor cell resistance against Bortezomib demand the development of improved and selective proteasome inhibitors. The potent proteasome inhibitors reported to date have been developed as aldehydes, boronates, vinylsulfones and expoxyketones and these compounds function through covalent modification of the N-terminal threonine residue of β-5 subunit. Small, drug-like synthetic proteasome inhibitors that are selective for cancer over normal cells are rare, but clearly would have a potential advantage over the existing inhibitors. PI-1833 was identified in our program as a ‘hit’ with in-vitro CT-L proteasome activity (IC50 = 0.58 μM). PI-1833 is a small molecule with oxadiazole pharmacophore and presents 3 points of diversity amenable for focused library synthesis. Lack of a reactive chemical moiety (or electrophilic moiety) to form proteasome adducts is an important feature of PI-1833. The first generation analogs of PI-1833 have shown promising SAR (in-vitro and in-vivo) toward proteasome inhibition with the IC50 values ranging from 0.3-0.7 μM. In this work we will present in-vitro and in-vivo structure activity relationship (SAR) data, synthesis and selectivity of a PI-1833 library and discuss the mode of proteasome inhibition (co-valent vs non co-valent) by this class of compounds.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1359. doi:10.1158/1538-7445.AM2011-1359
Abstract 1361: Fragment based drug discovery of selective inhibitors of Fibroblast Growth Factor Receptor (FGFR)
Authors: Saxty Gordon , Akkari R , Angibaud P , Arts J , Benderitter P , Berdini V , Bonnet P , Cleasby A , Embrechts W , Freyne E , Gilissen R , King P , Lacrampe J , Ligny Y , Madin A , Mcclue S , Mevellec L , Murray C W. , Newell H , Page M , Papanikos A , Perera T , Querolle O , Rees D C. , Rich S J. , Saalau-Bethell S M. , Sement E , Simmonet Y , Squires M , Tronel V , Ward G A. , Willems M , B Wroblowski , Thompson N T. 
Published: June 2012

Abstract
Recent data in a number of tumour types has implicated Fibroblast Growth Factor (FGF) and Fibroblast Growth Factor receptor (FGFR) signalling as being key to the molecular pathology of cancer.
A fragment screening campaign was conducted against the tyrosine kinase domain of FGFR1 to detect low molecular weight compounds that bound to the hinge region of the kinase. The screening produced several fragment inhibitors (molecular weight &lt;250 Da) in the micromolar range and their binding modes were confirmed by X-ray crystallography. We selected an imidazo[1,2-a]pyridine fragment that was 120 uM versus FGFR3 in the kinase inhibition bioassay. Subsequently, in the fragments-to-leads stage a detailed structural understanding of the binding interactions between the fragment and its protein kinase target, using X-ray crystallography, led to the identification of a 0.003 uM inhibitor of FGFR3 in the kinase bioassay, with significant selectivity versus VEGFR2 and FLT3.
The poster will focus on the description of previously undescribed compounds bearing an imidazo[1,2-a]pyridine core scaffold where selectivity versus other protein kinases, for example FLT3, is obtained using the X-ray crystal structure and structure-based design. In summary we will illustrate how X-ray crystallography and fragment-based drug design (FBDD) can be used to discover compounds with activity in an FGFR driven xenograft model when dosed by the oral route.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1361. doi:10.1158/1538-7445.AM2011-1361