bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2605: CE-TOFMS metabolome analysis for pharmacological responses to CPT-11 in colorectal cancer cells with different chemosensitivities
Authors: Nishimuta Akito , Suzuki Tetsuya , Arita Eri , Sugimoto Masahiro , Soga Tomoyoshi , Tanigawara Yusuke 
Published: February 2011

Abstract
Purpose: The topoisomerase I inhibitor irinotecan (CPT-11) is widely used for the treatment of metastatic colorectal cancer. However, mechanism to determine pharmacological response to CPT-11 is still unclear. We reported the application of a novel metabolomic analysis using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS) on the study of metabolic responses to anticancer agents (AACR #2563 and #4785, 2008 and #3764, 2009). The purpose of this study is to compare the metabolomic responses to SN-38, the active metabolite of CPT-11, between high-sensitive and low-sensitive colorectal cancer cells, for finding new biomarkers that can predict CPT-11 response.
Experimental Procedures: To elucidate metabolomic responses to SN-38, human colorectal carcinoma, HCT116 and HT29 cells were exposed to 50 nM SN-38. At time 0, 3, 8, and 24 h after SN-38 exposure, all intracellular metabolites were extracted by liquid-liquid extraction and simultaneously analyzed by CE-TOFMS. To find out low molecular weight compounds related to the sensitivity to SN-38, the metabolomic profiles were compared across the 8 colorectal cancer cell lines and sensitivity to SN-38 was investigated.
Results: The HCT116 cells were more sensitive to SN-38 than HT29. The intracellular metabolites of key pathways for cellular activity were quantitatively analyzed by CE-TOFMS, which included glycolysis, tricarboxylic acid (TCA) cycles, urea cycles, amino acid metabolism and pyrimidine metabolism. The intracellular levels of endogenous deoxyribonucleotides (dTTP and dCTP) increased after SN-38 exposure in both cells. In contrast, ribonucleotides such as CTP and UTP of RNA synthesis pathway were not affected by SN-38 exposure in either cell. These results imply the change in deoxyribonucleotide pool due to the disruption of DNA synthesis by topoisomerase I inhibition, the main anti-cancer mechanism of SN-38. It was also found that lactate and glycerol-3-phosphate were accumulated to a greater extent in HCT116 than in HT29. Furthermore, correlation analysis using 8 colorectal cancer cell lines revealed that the intracellular level of γ-aminobutyric acid (GABA) strongly correlated with cellular sensitivity to SN-38.
Conclusions: The present CE-TOFMS metabolome analysis created a new finding on metabolomic mechanisms for response to SN-38 by colorectal cancer cells with different chemosensitivities. GABA was found to be a potential low molecular weight biomarker that may be used for predicting CPT-11 response.
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 2605.
Abstract 2608: An intronic polymorphism determines TGF-alpha expression and is associated with cellular resistance to erlotinib
Authors: Wanqing Liu , Ratain Mark J. 
Published: February 2011

Abstract
An intronic polymorphism determines TGF-alpha expression and is associated with cellular resistance to erlotinib
Wanqing Liu, Mark J Ratain
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
Background
Responsiveness to EGFR-targeting agents has been demonstrated in lung cancer patients bearing EGFR mutations. However, the detailed mechanism underlying both sensitivity and resistance to these agents has not been completely revealed. Expression of transforming growth factor alpha (TGFA), one of the major EGFR ligands, appears to affect the inhibition potency of EGFR inhibitors. The aim of this study is to identify the genetic variants that may affect TGFA expression and confer susceptibility to response to EGFR-targeting agents.
Methods
Genome-wide genotyping of 100K single nucleotide polymorphisms (SNPs) had been previously performed in the NCI-60 cancer cell panel. SNPs in the TGFA gene region were selected to perform correlations with TGFA mRNA expression measured by real-time PCR. Confirmation of the SNP genotypes was performed by both sequencing and restriction enzyme digestion. The SNP genotype was correlated with cytotoxicity data of erlotinib and other EGFR inhibitors.
Results
A total of 10 SNPs in the TGFA gene were genotyped on the 100K SNP Chip. The genotypes were confirmed. A SNP (rs3821262 C/T) in the second intron of TGFA was significantly associated with decreased TGFA gene expression and cellular resistance to both erlotinib (p=0.01) and other 11 EGFR inhibitors (p=0.05) tested in the NCI-60.
Conclusion
The SNP rs3821262 C/T may contribute to cellular resistance to EGFR inhibitors by modulating the gene expression. However, since this is a hypothesis-generating study and the association was not adjusted for multiple testing, the finding must be validated further in both preclinical and clinical settings, in particular combined with mechanistic studies.
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 2608.
Abstract 2609: Nelfinavir induces liposarcoma apoptosis through inhibition of regulated intramembrane proteolysis of sterol regulatory element binding protein-1 and activating transcription factor 6
Authors: Guan Min , Jiang Chunling , Fousek Kristen N. , Guo Song , Chow Warren 
Published: February 2011

Abstract
We previously reported that nelfinavir induces a G1 cell cycle block and apoptosis selectively in liposarcoma cell lines as a consequence of up-regulation of SREBP-1 expression. We demonstrate now that nelfinavir-induced up-regulation of SREBP-1 and ATF6 is a direct result of inhibition of site-2 protease, which together with site-1 protease mediates regulated intramembrane proteolysis from their precursor state to their transcriptionally-active forms. The resulting endoplasmic reticulum stress and concurrent inhibition of the unfolded protein response induces caspase activation. Time-lapse, confocal microscopy studies demonstrate that nelfinavir inhibits the normal translocation of transfected SREBP-1-EGFP and ATF6-EGFP fusion proteins from the cytoplasm to the nucleus. siRNA-mediated knockdown of site-1 and/or site-2 protease leads to inhibition of SREBP-1 intracellular trafficking to the nucleus and reduces liposarcoma cell proliferation. Treatment of LiSa-2 liposarcoma cells with 4-(2-aminoethyl)benzenesulfonyl fluoride, a serine protease inhibitor of S1P did not affect SREBP-1 processing. In contrast, 1, 10-phenanthroline, an S2P-specific inhibitor, reproduces the molecular and biological phenotype observed in nelfinavir-treated cells, which confirms S2P is a target of nelfinavir. In vivo evaluation of nelfinavir in a murine liposarcoma xenograft model shows inhibition of tumor growth in the absence of significant toxicity. These results provide new insight into the mechanism of nelfinavir-mediated induction of ER stress and cell death in liposarcomas and are the first report to therapeutically target S2P against cancer.
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 2609.
Abstract 2662: Pharmacokinetics, metabolism and tissue distribution of the nitric oxide-donating prodrug JS-K following administration in liposomes
Authors: Buhrow Sarah A. , Reid Joel M. , Walden Chad A. , Jia Lee , Davis Myrtle , Keefer Larry K. , Barazi Heba , Ames Matthew M. 
Published: February 2011

Abstract
The diazeniumdiolate O2-(2,4-dinitrophenyl)-1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2diolate (JS-K, NSC 724771) is a nitric oxide (NO)-donating prodrug that was designed to release NO upon reaction with glutathione-S-transferase which is overexpressed in some tumors. We demonstrated that JS-K reacts with nucleophiles in biological fluids and has an extremely short half-life in mice. The purpose of the study was to test the hypothesis that liposomal encapsulation improves the in vivo half-life, tissue distribution and acute toxicity profile of JS-K. We investigated the pharmacokinetics of [3H]JS-K in CD mice administered the drug in DMSO or DMPC (dimyristoylphosphatidylcholine) liposomes (20:1 molar ratio of DMPC: JS-K) and in tumor-bearing athymic nu/nu NCr mice administered the radiolabeled drug in DMPC liposomes. The terminal elimination half-life of total radioactivity (2 hours) was similar for both formulations. We did not detect [3H]JS-K in any plasma or red blood cell samples from mice administered 6 mg/kg JS-K in DMSO and only trace amounts of [3H]JS-K were detected in samples collected at the earliest time-points from mice administered 6 mg/kg JS-K in DMPC liposomes. Small amounts of radioactivity, presumably associated with JS-K metabolites, were detected at the solvent front of HPLC chromatograms. Very little radioactivity and no JS-K was detected in tumor samples. Finally, we developed an LC/MS/MS assay to investigate formation of JS-K metabolites in biological samples and used that method to measure concentrations of JS-K and its metabolites in plasma, red blood cells, liver tissue and tumor tissue collected from tumor-bearing mice administered 3 mg/kg or 6 mg/kg JS-K in DMPC liposomes. We confirmed extremely rapid in vivo degradation of JS-K in the systemic circulation following intravenous administration and rapid formation of several expected metabolites including high concentrations of the glutathione conjugate of the dinitrophenol moiety and piperazine. Supported by NCI Contract NO1-CM-52206.
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 2662.
Abstract 2670: CONFORMATIONAL PLASTICITY OF HUMAN THYMIDYLATE SYNTHASE
Authors: LUO BEIBEI , Berger Sondra H. 
Published: February 2011

Abstract
Thymidylate synthase (TS), catalyzes the reaction that forms dTMP from dUMP. Previous data suggested that human thymidylate synthase (hTS) exists in two major conformations, active and inactive. Two hTS mutants were created to mimic the active and inactive forms. The mutant, designated R163K, has an arginine to lysine substitution at residue 163 and crystallizes in an active conformation in the native state. The other one, A191K, has an alanine to lysine substitution at residue 191 and is stabilized in the inactive form. To further test whether the mutants exhibit different conformations in solution, circular dichroism was used to compare solution structures and detect the effects of ligand binding. Relative to hTS, the CD spectra of both R163K and A191K showed a decreased ellipticity. Upon ligation with dUMP, A191K exhibited a further decrease in ellipticity and showed no apparent response to phosphate. In contrast, the ellipticity of R163K was increased by phosphate and dUMP produced a further increase in ellipticity. Crystal structures suggested that the catalytic thiol of R163K is more susceptible to modification by oxidation compared to hTS. Thus, we postulated that the inactive form functions to sequester the catalytic thiol from oxidation. To test the hypothesis, we conducted studies of the rate of modification of purified enzymes with the thiol-reactive agent, 5, 5′-dithiobis(2-nitrobenzoic acid) (DTNB). Relative to hTS, a slight increase in oxidation rate was observed in the active-stabilized mutant; however, the rate of catalytic inactivation of hTS was faster. In vivo, TS-deficient transfectants expressing R163K were more sensitive to oxidative stress relative to cells expressing wt hTS. The data provide preliminary evidence of a protective role of the inactive form under the oxidative stress although the basis for this effect remains unclear.
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 2670.
Abstract 2687: Development of a new, highly sensitive assay for circulating tumor cell (CTC) detection based on the CellSearch® CTC Profile Kit enrichment and laser scanning cytometry analysis
Authors: Melnikova Vladislava O. , Liu Wen , Zhang Yujian , Hong David S. , Davis Darren W. 
Published: February 2011

Abstract
The presence of CTCs in the peripheral blood, as detected by the FDA-approved CellSearch® CTC Kit, is associated with decreased overall and progression free survival in patients with metastatic breast, prostate and colorectal cancers. In addition to CTC enumeration, CellSearch® CTC Kit provides a unique tool for CTC biomarker analysis in cancers of epithelial origin (CD45—, EpCAM+, and cytokeratins (CK) 8,18-positive and/or 19-positive). Considerable cell loss is suspected to occur at many of the automated steps of the CellSearch® CTC process, resulting in undermined recovery of CTCs. Herein, we demonstrate an improved, highly sensitive approach for CTC enumeration, which is based on the CellSearch® CTC Profile Kit and immunofluorescent analysis using LSC. The initial blood processing was conducted using the CellSearch® CTC Profile Kit from Veridex and the CellTracks® AutoPrep® system, which allowed recovery of the EpCAM+ cells directly from the instrument. Next, EpCAM+ cell population was subjected to manual immunofluorescent labeling with antibodies against CK and CD45, and CTCs were enumerated by LSC, based on the standard CellSearch® CTC criteria. When we compared this new method to standard CTC enumeration in patients with various cancer types including head and neck, renal cell, basal cell, prostate, non-small cell lung, sebaceous gland and ovarian cancers, we consistently detected higher CTC counts in samples analyzed with the new method. Indeed, 88% of patients (79 out of 90) were CTC-negative based on the standard analysis, while only 37% of patients were CTC-negative based on the CTC Profile Kit/LSC data. We next conducted a side-by-side comparison of the two techniques in patients with hepatocellular carcinoma (HCC, EpCAM-low) and prostate cancer (EpCAM+). CTC Profile Kit/LSC method demonstrated up to a 470% increased CTC recovery in the prostate cancer samples. Remarkably, it also allowed isolation of CTCs from the CTC-negative (as detected by the standard kit) HCC and prostate cancer samples. Finally, the new CTC enumeration method consistently yielded higher CTC counts in patients enrolled in a Phase I clinical trial of Bevacizumab and Cediranib. Importantly, our preliminary analysis indicated that changes in CTC counts from baseline to 24 h post-therapy, as measured by the new method, may correlate with changes in tumor size. In conclusion, we developed a new CellSearch® CTC Profile Kit/LSC-based method that offers higher sensitivity of CTC recovery and thus provides a broader capability for downstream molecular characterization.
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 2687.
Abstract 2703: Loss of dependence on EGFR signaling by upregulation of Mig6 confers drug resistance to erlotinib
Authors: Chang Xiaofei , Chatterjee Aditi , Huang Shyhmin , Kim Myoung Sook , Shao Chunbo , Monitto Constance L. , Ha Patrick K. , Hidalgo Manuel , Harari Paul M. , Berman David M. , Bedi Atul , Sidransky David 
Published: February 2011

Abstract
We sought to elucidate mechanisms of resistance to epidermal growth factor receptor (EGFR)-targeted therapies and to identify markers that could better distinguish resistant from sensitive patients. Here we show that mitogen-inducible gene 6 (Mig6), a negative regulator of EGFR, was selectively upregulated during the evolution of resistance to the EGFR tyrosine kinase inhibitor (TKI) erlotinib in lung and head and neck cancer cell lines. Mig6 was a major determinant of EGFR activity in panels of cancer cell lines of different tissue origins, and in direct validation of approved human use, in a unique collection of directly xenografted human lung and pancreas tumors. Our work highlights the importance of cellular negative regulators of EGFR in predicting and subverting TKI responsiveness, and identifies the ratio of Mig6 to EGFR, rather than the absolute expression of either protein alone, to be a predictor of tumor cell response to erlotinib.
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 2703.
Abstract 2783: Mammotrophic hormone score and risk of postmenopausal breast cancer
Authors: Tworoger Shelley S. , Eliassen Heather , Rosner Bernard , Hankinson Susan E. 
Published: February 2011

Abstract
Sex hormones and prolactin have been positively associated with risk of breast cancer among postmenopausal women. However two small studies suggested that having multiple hormones above the age-adjusted mean level did not further increase the risk of breast cancer beyond having only one hormone above the mean. This suggests a possible threshold effect, such that these hormones may be permissive with respect to breast cancer growth and an evaluation of hormones levels at the low end of the distribution may be most informative. The goal of this study was to evaluate the combined effect of multiple hormones, including estradiol, estrone, estrone sulfate, testosterone, androstenedione, DHEA, DHEAS, and prolactin, in relation to postmenopausal breast cancer risk. We conducted a nested case-control study in the Nurses' Health Study including cases of postmenopausal breast cancer who were not using postmenopausal hormones at blood collection in 1990 and were diagnosed after blood collection but before June 1, 1998 and their matched controls. We examined the relationship between the number of hormones in which levels were above age- and batch-adjusted means (as determined in controls and referred to as the “hormone score”) and risk of breast cancer overall using conditional logistic regression adjusting for age at menopause, body mass index (BMI) at age 18, history of benign breast disease, and family history of breast cancer. We also examined estrogen receptor (ER) positive cases only using unconditional logistic regression. Overall, 265 cases (189 ER+) and 541 matched controls had measured levels for all eight hormones. The mean hormone score was 4.6 (SD=2.3) in cases and 3.9 (SD=2.4) in controls (p&lt;0.001). There was a statistically significant 16% increase in risk for a one unit increase in the hormone score with risk of breast cancer overall (95% CI: 1.08-1.24, p-trend&lt;0.001) and a 19% increase for ER+ tumors (95% CI: 1.10-1.28, p-trend&lt;0.001). Women with a hormone score of 6-8 versus 0 had a significantly increased risk of breast cancer overall (RR=2.67, 95% CI: 1.26-5.62) and of ER+ disease (RR=5.30, 95% CI: 1.18-15.5). For ER+ tumors, women with a score of 3-5 versus 0 also had an increased risk (RR=3.12, 95% CI: 1.08-9.02). Despite the somewhat small number of cases, our data support that the risk of postmenopausal breast cancer increases linearly as the number of hormones with high levels rises. This suggests that proliferation and other carcinogenic processes may be sensitive to the influence of multiple mammotrophic hormones simultaneously. Further, this information could be used to develop improved risk prediction models.
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 2783.
Abstract 2790: Prospective study of urinary prostaglandin E2 metabolite and lung cancer risk
Authors: Cai Qiuyin , Gao Yu-Tang , Wen Wanqing , Milne Ginger L. , Yang Gong , Ji Bu-Tian , Rothman Nathaniel , Li Hong-Lan , Shu Xiao-Ou , Chow Wong-Ho , Zheng Wei 
Published: February 2011

Abstract
Cumulative evidence from both in vitro and animal studies suggests that cyclooxygenase-2 (COX-2) may be involved in the development and progression of lung cancer. Overproduction of prostaglandin E synthase and prostaglandin E2 (PGE2), one of the end products of the COX-2 pathway, has been implicated in the pathogenesis of non-small cell lung cancer. It is believed that the pro-inflammation effects of COX-2 pathway are largely mediated through PGE2. PGE2 is quickly converted to 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), a major PGE2 metabolite and excreted from urine. In this study, we evaluated the association of urinary PGE-M levels and lung cancer risk. A nested case-control study was conducted within the Shanghai Women's Health Study, in which 74,942 Chinese women aged 40-70 years were recruited from 1997 to 2000 and followed up for up to 10 years. Urinary PGE-M in 192 incident lung cancer patients were compared to 192 matched controls. The baseline level of urinary PGE-M was comparable between cases and controls. Excluding 20 case-control pairs who were diagnosed with lung cancer within one year of follow-up or excluding 22 case-control pairs who ever smoked did not change the null association. No interaction was found between PGE-M and smoking or passive smoking in relation to lung cancer risk. Our data suggest that the PGE2 pathway may not play a major role in lung cancer development in non-smoking women. Further studies are being conducted to evaluate whether genetic variations in the PGE2 pathway will modify the urinary PGE-M and lung cancer association. Given the substantial laboratory evidence, further evaluation of the COX-2 pathway in lung cancer pathogenesis, including other urinary biomarkers and genetic variations, may be warranted.
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 2790.