bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2693: Pharmacogenetic determinants associated with sunitinib-induced toxicity and ethnic difference in Korean patients with metastatic renal cell carcinoma
Authors: Kim Hye Ryun 
Published: August 2012

Abstract
Purpose: The aim of this study was to investigate the pharmacogenetic determinants of sunitinib-related toxicity and ethnic difference in metastatic renal cell carcinoma (mRCC) among Korean patients. Experimental Design: A pharmacogenetic study was performed in 65 patients with mRCC treated with sunitinib (50mg orally once daily for 4 weeks-on/2 weeks-off). Detailed data regarding the toxicity of sunitinib, including thrombocytopenia, neutropenia, anemia, and hand-foot syndrome (HFS) were prospectively collected in a clinical trial program (n=38) or general oncology practice (n=27) using sunitinib. A total of 12 genetic polymorphisms in 7 candidate genes (CYP1A1, ABCG2, ABCB1, PDGFRα, VEGFR2, RET, and FLT3) were analyzed for an association with treatment-related toxicity using Pearson-χ2 test. Results: Common grade 3 or 4 treatment-related toxicities were thrombocytopenia (36.9%), neutropenia (18.4%), anemia (7.7%), and HFS (12.3%). Patients carrying an ABCG2 421 A/A genotype developed significantly more grade 3 or 4 thrombocytopenia, neutropenia, and HFS: odds ratio [OR] 10.15; P=0.03, thrombocytopenia, OR 17.33; P=0.003, neutropenia, OR 33.60; and P=0.005, HFS. Conclusion: c.421C&gt;A genetic polymorphism in the ABCG2 gene may be most associated with the risk of sunitinib-related toxicity in mRCC patients. Considering the high frequency of ABCG2 c.421C&gt;A SNP in Asian individuals, this may lead to differential toxicities among ethnic groups.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2693. doi:1538-7445.AM2012-2693
Abstract 2729: Suppression of hematogenous metastasis by mouse and murine/human chimeric anti-Aggrus/podoplanin antibodies
Authors: Takagi Satoshi , Fujita Naoya 
Published: August 2012

Abstract
Tumor cell-induced platelet aggregation has been known to facilitate hematogenous metastasis by increasing the arrest of tumor cell emboli in the microvasculature. We have previously established metastatic variants of cancer cells and identified Aggrus (also known as podoplanin, T1alpha, gp36) as a platelet aggregation-inducing factor expressed on the surface of highly metastatic variants. Aggrus, a type-I transmembrane sialomucin-like glycoprotein, induced platelet activation via interaction with one of its counter receptor CLEC-2 (C-type lectin-like receptor 2) expressed on platelet surface. Thus, Aggrus-induced platelet aggregation did not require any plasma components. Moreover, Aggrus has been shown to be up-regulated in many different types of cancers and to be associated with poor outcome. Thus, Aggrus must be a useful cancer specific antigen in addition to a useful therapeutic target for developing hematogenous metastasis inhibitors. In this study, we established an anti-human Aggrus monoclonal antibody, designated as P2-0, and investigated its potential as a hematogenous metastasis inhibitor. We observed that P2-0 antibody could inhibit Aggrus-CLEC-2 interaction detected by in vitro competition assay and could suppress Aggrus-induced platelet aggregation in a concentration-dependent manner. Moreover, P2-0 antibody decreased the number of Aggrus-mediated pulmonary metastatic foci in in vivo experimental mouse model. We then cloned complementarity-determining region of P2-0 antibody and generated murine/human chimeric P2-0 antibody. We revealed that chimeric P2-0 antibody retained Aggrus-neutralizing activity and inhibited the experimental pulmonary metastasis of cancer cells that endogenously expressed Aggrus on their surface. These data indicate that P2-0 antibody and its chimeric antibody are useful as inhibitors of Aggrus-mediated hematogenous metastasis and expected to be applied for the clinical examination of Aggrus-targeted cancer therapy. This study was supported in part by a grant from the Program for the Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation, Japan.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2729. doi:1538-7445.AM2012-2729
Abstract 273: Transcriptional regulation of L1CAM in endometrial cancer
Authors: Schirmer Uwe 
Published: August 2012

Abstract
The L1 cell adhesion molecule (L1CAM, CD171) was initially described as a cell surface protein in the developing nervous system involved in neural outgrowth and axon guidance. During the last years it became evident that high expression levels of L1CAM are observed in many human carcinomas and are linked to tumor progression. L1CAM expression in tumors can augment cell motility and invasive potential and lead to constitutive NFκB activation. We showed before that in endometrial cancer (EC) the expression of L1CAM was correlated with poor prognosis. ECs can be subdivided in two types; a less aggressive type I and a highly aggressive type II. We showed that L1CAM expression was absent in type I ECs, whereas all cases of type II tumors (n=272) were L1CAM positive. We also provided evidence that in L1CAM-negative EC cell lines L1CAM expression can be upregulated by TGF-b1 treatment involving the transcription factor SLUG. In the present study, we have investigated additional mechanisms that can affect L1CAM expression. These mechanisms involve the modification of histone proteins and their packaging to the DNA as well as the direct modification of the DNA by DNA-methyltransferases (DNMTs). We show that the treatment of EC cell lines with Histon-deacetylase-Inhibitors (HDACIs) and/or DNMT inhibitors lead to increased L1CAM expression at the mRNA and protein level. Furthermore, we observed that the methylation pattern of the L1CAM-promoter differed between L1CAM positive and negative cell lines. The RE-1 silencing transcription factor (REST) complex seems to be responsible for the silencing of the L1CAM expression in non-neuronal tissues. The REST complex is associated with chromatin-remodeling complexes, the recruitment of HDACs as well as DNMTs and thereby leads to the silencing of the respective promoter element. We observed that the knockdown of REST in L1CAM negative EC cell lines leads to a dramatic increase in L1CAM expression. Likewise the overexpression of REST in L1CAM positive EC cell lines diminished L1CAM expression. We conclude that the loss or reduced expression of REST in concert with epigenetic elements could represent an additional and novel mechanism to cause aberrant L1CAM expression in ECs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 273. doi:1538-7445.AM2012-273
Abstract 2735: Effects of metformin on a non-small cell lung cancer cell line with an EGFR mutation
Authors: Kitazono Satoru , Takiguchi Yuichi , Ashinuma Hironori , Kitazono Miyako , Kitamura Atsushi , Tada Yuji , Kurosu Katushi , Sakaida Emiko , Sekine Ikuo , Tatsumi Koichiro 
Published: August 2012

Abstract
Background:Metformin, one of the most widely prescribed oral agents for treating diabetes mellitus, has been speculated to have antineoplastic effects. The effects, however, have not been fully understood. Experimental Design:A human non-small-cell lung cancer cell line, PC9 (with an EGFR mutation of the exon 19 E746-A750 deletion), was used to evaluate antineoplastic effects of metformin in vitro and in vivo. For in vitro experiments, the cells were exposed to metformin, gefitinib or cisplatin to observe inhibitory effects on cell proliferation. At 24, 48 and 72 hours after the start of the culture with the agents, cell cycle analysis, measurements of caspase 3, 8 and 9 activities, and evaluation with Hoechst staining and APOPercentage TM assay, respectively, were performed. For in vivo experiments in SCID mouse with a xenograft subcutaneous tumor, gefitinib (150 mg/kg, oral gavage) or metformin (250 mg/kg, i.p.) was daily administered to the mice. Results:Gefitinib at a concentration of 0.03 μM, cisplatin of 1.5 μg/ml and metformin of 10 mM exerted equivalent inhibitory effects on cell proliferation in vitro. At these particular concentrations, metformin did not induce significant apoptosis over control as assessed by Hoechst staining, APOPercent assay and caspase 3 activity, whereas gefitinib and cisplatin did induce apoptosis dramatically. Metformin failed to alter cell cycle distribution, whereas gefitinib and cisplatin caused G1/G0 an S phase accumulation, respectively. Metformin did not inhibit growth of already grown subcutaneous tumors, whereas the tumors shrank dramatically with gefitinib treatment. After almost complete disappearance of the tumors by gefitinib, however, they regrew by gefitinib withdrawal. Metformin did significantly suppress the regrowth of the tumors after gefitinib withdrawal. Conclusions: Metformin has inhibitory effects on growth of a human non-small cell lung cancer cell line with a sensitive EGFR mutation in vitro and in vivo, and its mechanism may not depend on apoptosis or cell cycle alteration. Although the agent does not suppress growth of already grown tumors, it significantly suppresses tumor regrowth after gefitinib withdrawal.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2735. doi:1538-7445.AM2012-2735
Abstract 2737: Anti-proliferative action of metformin on various types of human lung cancer cell lines
Authors: Ashinuma Hironori , Takiguchi Yuichi , Kitazono Satoru , Kitazono-Saitoh Miyako , Kitamura Atsushi , Tada Yuji , Kurosu Katsushi , Sakaida Emiko , Sekine Ikuo , Tanabe Nobuhiro , Tatsumi Koichiro 
Published: August 2012

Abstract
[Background] Metformin has a potential to inhibit tumor growth in various cancer cell lines in vitro and in vivo. [Purpose] To elucidate anti-proliferative actions of the agent on various types of human lung cancer cell lines, and to evaluate combined effects with cisplatin. [Methods] Cell lines used consisted of four human lung cancer cell lines, RERF-LC-AI (squamous cell carcinoma), A549 (adenocarcinoma), IA-5 (large cell carcinoma) and WA-hT (small cell carcinoma). Colonogenic assay was employed to evaluate colonogenicity with exposure to metformin for 1, 24 hours and 10 days. In cell surviving assay, 100,000 cells per plate were cultured for 4 days with metformin and/or cisplatin, and survived cells were counted. [Results] Metformin inhibited colonogenecity in every cell line in a dose-dependent manner when cells were exposed to the agent for 10 days, whereas 1- and 24-hour exposure yielded not significant or only mild effects, with the degree varied depending on cell lines. With cell surviving assay at the metformin concentrations where 70% (IC70) and 30% (IC30) of the cells survived for each cell line, apoptosis was not increased over control groups in every cell line except for WA-hT that showed significant increase in apoptosis with metformin. Significant alteration in cell cycle distribution with the agent was not observed in all of the 4 cell lines. For evaluating combination treatment consisting of metformin and cisplatin, cisplatin at doses of IC50 and IC10 was combined with metformin. Inhibitory effects of metformin on cell proliferation were slightly suppressed with cisplatin at its dose of IC50 in all except for in A549. High dose (IC10) of cisplatin almost completely countervailed or even reversed the metformin effects in all cell lines, again except for A549 where a modest but significant sub-additive effect was observed. [Conclusions] Metformin has anti-proliferative effects on various types of human lung cancer cell lines. Although apoptosis was observed only in a small-cell lung cancer cell line, its effects may not depend on apoptosis in other 3 cell lines. Alteration of cell cycle distribution was not observed in all cell lines. Metformin and cisplatin were antagonistic especially with higher dose cisplatin.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2737. doi:1538-7445.AM2012-2737
Abstract 2753: The addition of low dose 17-DMAG to BIBW-2992 effectively inhibits lung cancer cells with acquired resistance by T790M mutation
Authors: Rho Jin Kyung , Choi Yun Jung , Kim Sun Ye , Choi Chang-Min , Lee Jae Cheol 
Published: August 2012

Abstract
The majority of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is caused by secondary T790M mutation. We established gefitinib or erlotinib-resistant cells which acquired different proportions of T790M from PC-9 cells with activating EGFR mutation. Anti-cancer effects of EGFR modulation and strategies overcoming resistance were investigated. The amount of T790M and EGFR gene copy number were proportional to increase of resistance. BIBW-2992, an irreversible EGFR-TKI, could suppress the growth and survival of cells harboring lower level of T790M while it failed in cells with higher level of T790M although p-EGFR was completely down-regulated in both, suggesting blocking of phosphorylation of EGFR is not sufficient to inhibit these cells. However, EGFR siRNA treatment could inhibit cell growth regardless of T790M level and resistance showing that EGFR dependency would be persistent. 17-DMAG, a HSP90 inhibitor, also effectively controlled both resistant cells. Considering a report showing that a HSP90 inhibitor was not clinically effective possibly because of inadequate dose, the efficacy of low dose 17-DMAG was examined. Interestingly, we found that combined treatment of BIBW-2992 with low dose 17-DMAG was very effective even in cells with higher level of T790M although either of both showed no activity in single treatment suggesting it would be one of promising strategies with immediate clinical implications overcoming T790M-mediated resistance. Further investigations on exact mechanism should be pursued even though capability of HSP90 inhibitor to modulate NF-kB signaling can be one of possible explanations.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2753. doi:1538-7445.AM2012-2753
Abstract 2754: Cinnamoyl quinolines are novel autophagy inhibitors and enhance antitumor activity of 2-deoxyglucose
Authors: Yih Ling-Huei , Kakadiya Rajesh , Wu Yi-Chen , Kuo Hsiao-Hui , Su Tsann-Long 
Published: August 2012

Abstract
Cinnamides exhibit a variety of biological properties including antineoplastic, antiallergic, and anti-infective activities etc. Modifications of the amide function of cinnamides by linking with aliphatic or heterocyclic moieties results in the formation of cinnamoyl derivatives with anticancer activities. In the present study, we prepared a series of cinnamoyl quinolines and evaluated their antitumor activity in a panel of cancer cell lines. These derivatives reduced cancer cell viability by inducing apoptosis and showed little to no cross-resistance to vinblastine- or cisplatin-induced multidrug resistance. Interestingly, the cinnamoyl-quinoline-6-yl derivatives (BO-2110 and BO-2112) induced cytoplasmic vacuolization and the processing and recruitment of microtubule-associated protein 1 light chain 3 (LC3) to autophagosomes. However, these agents caused the accumulation and aggregation of p62/SQSTM1. Co-treatment of cinnamoyl-quinoline-6-yl derivatives with bafilomycin A1 did not induced a further increase in p62/SQSTM1 accumulation. These results indicated that cinnamoyl-quinoline-6-yl derivatives blocked autophagy. Since autophagy enables cancer cells to temporarily avoid cell death when nutrient deprivation or exposing to chemotherapeutic agents, cinnamoyl quinolines may sensitize cancer cells to death and augment chemotherapy-induced apoptosis. Co-treatment of these derivatives with 2-deoxyglucose (2DG, glycolysis inhibitor), but not cisplatin (DNA alkylating agent), camptothecin (Topo I inhibitor), doxorubicin or etoposide (Topo II inhibitor), significantly enhanced cell death in the tested tumor cell lines. Collectively, these results suggest that BO-2110 and BO-2112 are effective autophagy inhibitors and promising candidates that may be used in combination with 2DG for treating cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2754. doi:1538-7445.AM2012-2754
Abstract 2769: The development of 19-substituted benzoquinone ansamycins as potential anticancer drugs
Authors: Chang Chuan-Hsin , Kitson Russell , Siegel David , Moody Christopher J. , Ross David 
Published: August 2012

Abstract
Benzoquinone ansamycins (BQA's) were the first class of Hsp90 inhibitors developed but the use of the prototype agent geldanamycin was limited by hepatotoxicity. One major mechanism of toxicity of the BQA class is manifested via the electrophilic properties of the quinone and alkylation of cellular nucleophiles at the 19-position. We developed novel 19-substituted BQA's in the geldanamycin (GA), 17-AAG and 17-DMAG series as a means to prevent arylation of cellular nucleophiles. 19-substituted BQA's inhibited recombinant Hsp90 and did not react with thiols at the 19-position while marked thiol reactivity could be detected using their parent quinones. We examined the effects of different substitution patterns at the 19-position on the ability of BQAs to inhibit Hsp90 and induce growth inhibitory effects in breast cancer cell lines. We found that both 19-phenyl and 19-methyl BQA's in the 17-AAG, 17-DMAG and GA series were effective inhibitors of purified Hsp90 as demonstrated using an ATPase assay particularly in the presence of NQO1 to generate the hydroquinone ansamycin. Only 19-phenyl substituted BQAs were effective growth inhibitory agents in breast cancer cell lines using an MTT assay while 19-methyl substituted BQAs in the GA, 17-AAG and 17-DMAG series demonstrated only modest growth inhibition. The growth inhibitory effects of 19-phenyl BQAs were potentiated in cells containing high NQO1. Notably, 19-phenyl DMAG had similar growth inhibitory and apoptotic effects as its parent quinone, DMAG. These data demonstrate that the 19-phenyl BQAs had marked growth inhibitory, apoptotic, and client protein expression effect in breast cancer cells compared to 19-methyl BQAs (Supported by CA 51210).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2769. doi:1538-7445.AM2012-2769
Abstract 2771: HSP90 inhibitor NVP-AUY922 exhibits the potent antiproliferative effect in gastrointestinal cancer cells with a lack of PTEN expression
Authors: Takaoka Munenori , Bao Xiaohong , Hao Huifang , Fukazawa Takuya , Yamatsuji Tomoki , Tomono Yasuko , Sakurama Kazufumi , Naomoto Yoshio 
Published: August 2012

Abstract
Background: The heat shock protein 90 (HSP90), a molecular chaperone, has provoked great interest as a promising molecular target for cancer treatment, since it is involved in regulating the conformation, stability and functions of key oncogenic proteins. At present, a variety of chemical compounds targeting HSP90 have been developed and have shown convincing anti-neoplastic activity in various preclinical tumor models. Several inhibitors of HSP90 have been reported exhibiting more antitumor efficacy in PTEN-null tumor xenograft. The aim of our study was to evaluate the antitumor effects of a novel HSP90 inhibitor, NVP-AUY922, in human malignant cells, especially in PTEN-null cancer cells. Materials and Methods: Human esophageal cancer (TE-1, TE-4, TE-8, TE-10), gastric cancer (NUGC-3, NUGC-3/IL), pancreatic cancer (PANC-1, MIAPACA-2, Bxpc3) and mutant c-kit-driven lymphocytes (Ba/F3-KE11, Ba/F3-K642, Ba/F3-820Mz), mimicking gastrointestinal stromal tumor cells, were examined. WST assay and/or trypan blue exclusion assay were conducted to assess the anti-proliferation effects of NVP-AUY922 in those cells mentioned above. The activity of cell growth-related molecules such as AKT, ERK, and PTEN were investigated by western blot analysis. Genetic modification using siRNA and expression vector were applied for silencing and overexpression of PTEN, respectively, in cancer cells. Results: Cell viability assays showed that NVP-AUY922 potently inhibits the proliferation of human cancer cell lines, regardless of 5-FU resistance or c-Kit mutation, by which the sensitivity to imatinib can be affected. PTEN-null TE-4 cells exhibited more sensitivity to NVP-AUY922. Interestingly, The sensitivity to NVP-AUY922 was increased by silencing PTEN expression in intact PTEN-expressing TE-10 cells and decreased by exogenous transduction of PTEN in TE-4 cells. Furthermore, NVP-AUY922 significantly inhibited the activity of AKT and ERK in TE-4 cells, but not in TE-10 cells. Conclusion: Inhibition of Hsp90 function by NVP-AUY922 exhibited strong cytotoxicity against most of the cancer cells, including some anticancer drug-resistant cells, revealing its potential for a novel therapeutic alternative to cancer treatment. In addition, this study suggests that the expression status of PTEN determines the sensitivity to HSP90 inhibitor for cancer treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2771. doi:1538-7445.AM2012-2771