bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 757: Development and validation of an HPLC-UV method for lapatinib quantification in human plasma
Authors: Escudero Vanesa , Valenzuela Belén , Rebollo Joseba , Sureda Manuel , Brugarolas Antonio 
Published: August 2012

Abstract
Background and objective: Lapatinib is a 4-anilinoquinazoline that can reversible and selectively inhibit both human epidermal growth factor receptor (EGFR, HER1) and human epidermal growth factor receptor type 2 (HER2) tyrosine kinases. As others tyrosine kinase inhibitors (TKIs), lapatinib shows a large interindividual variability in its pharmacokinetics (PK). So, the variability in drug exposure to TKIs may contribute to the variation in anti-cancer PD effect. Causes for this PK variability are manifold during the different processes of ADME. Up to date, only mass spectrometry detection is currently available to determine lapatinib in human plasma. The purpose of this study was to develop a simple and sensitive high-performance liquid chromatographic method with UV-Visible detection for quantification of lapatinib concentrations in human plasma to allow therapeutic drug monitoring (TDM) of lapatinib in cancer patients. Methods: After a liquid-liquid extraction with acetonitrile, lapatinib and sorafenib (internal standard, IS) are separated on Ultrabase C18 column using a mobile phase consisting of a mixture of 0.02 M ammonium acetate and acetonitrile in a proportion 47:53 pumped at a constant flow rate of 1.2 mL/min. The column was maintained at 25°C and the eluent was monitored at a wavelength of 260 nm. Results: The calibration curve was linear in the range 200-10000 ng/mL. The limit of quantification was determined to be 200 ng/mL. Lapatinib and IS retention times were 3.2 and 10.6 min, respectively. Inter- and intra-day coefficients of variation were less than 7%. The mean extraction recovery from plasma was higher than 86%. Conclusion: The simple, rapid and sensitive HPLC-UV method developed and validated for the measurement of lapatinib in human plasma using sorafenib as IS can be applied easily in routine clinical practice for the TDM of lapatinib.
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 757. doi:1538-7445.AM2012-757
Abstract 77: Study of the effect of MAPRE2 on human lung adenocarcinoma cell migration and invasion
Authors: Lai Yi-Hua , Chen Ching-Hsien , Tsai Meng-Feng , Chen Huei-Wen , Su Kang-Yi , Yuan Ang , Chen Jeremy J.W. 
Published: August 2012

Abstract
Lung cancer is the most malignant disease which makes lots of people dead worldwide. More and more evidences showed that cancers might arise from chromosome alteration, including amplification or deletion. Our previous study integrating microarray-based comparative genomic hybridization and affymetrix gene expression profiles identified a potential candidate gene, MAPRE2, in a lung cancer cell line model with different invasion capability. MAPRE2 (Microtubule-associated protein RP/EB family member 2) is usually located on microtubule and interactes with tumor suppress gene APC (adenomatous polyposis coli). MAPRE2 might be involved in microtubule polymerization, cell migration and tumorigenesis of colorectal cancers, but its function is unclear. The purpose of this study is to investigate the effects of MAPRE2 on cancer cell function. The results of real-time PCR and western blotting showed that DNA copy number, RNA and protein level of MAPRE2 were higher in low invasive lung cancer cells than in highly invasive cells. Immunofluorescence assay indicated that the distribution of MAPRE2 protein was predominant in cytoplasm. Furthermore, overexpression of MAPRE2 could inhibit cancer cell proliferation, anchorage- dependent and -independent growth, cell motility, invasion ability in vitro and tumor growth and metastasis in vivo. On the contrary, silencing MAPRE2 enhanced lung cancer cell proliferation and invasion ability. Consider the whole map of MAPRE2-regulated signalling, transcriptomic analysis was performed and the results showed that MAPRE2 could affect 1039 genes (ANOVA, FDR&lt; 0.05) which are dominantly involved in cell cycle and adhesion-related biological signalling, such as MAPK, focal adhesion and tight junction pathways. Our results suggested that MAPRE2 might play a significant role in MAPRE2-mediated pathways to suppress tumorigenesis and metastasis.
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 77. doi:1538-7445.AM2012-77
Abstract 776: Sensitization of glioblastoma cells to temozolomide induced antitumor effect by PLGA-aspirin microsphere through modulation of β-catenin transactivation
Authors: Shi Zhendong , Qian Xiaomin , Han Lei , Zhang Kailiang , Zhu Shanjun , Zhu Jialin , Lan Fengming , Zhang Junxia , Zhang Chunzhi , Pu Peiyu , Yuan Xubo , Kang Chunsheng 
Published: August 2012

Abstract
Malignant gliomas are the most prevalent and deadliest brain neoplasms. Although temozolomide (TMZ) was currently used for treating glioblastoma patients, the recurrence was commonly existed due to the acquired therapeutic resistance. Thus the combination chemotherapy with TMZ is considered a promising therapeutic strategy in overcoming therapeutic resistance and improving treatment efficacy. In this study, we performed PLGA microspheres of aspirin and TMZ by spray drying technique and detected their cytotoxicity to glioblastoma cells. In vitro assay, PLGA-aspirin (PLGA-A) microsphere treatment revealed a slight inhibition of proliferation, invasion, as well as slightly induced apoptosis of A172 and U87 cells through inhibition of β-catenin transactivation in comparison with PLGA microsphere and Control group. In addition, the limited antitumor effect was also demonstrated in vivo. However, PLGA-aspirin-temozolomide (PLGA-A-T) microsphere treatment group displayed enhancing antitumor efficacy compared with PLGA-temozolomide (PLGA-T) microsphere group. IC50 values were dramatically decreased in cells treated with PLGA-A-T microsphere, to a greater extent than those treated with PLGA-A microsphere. Meanwhile, the PLGA-A-T microsphere significantly enhanced apoptosis in both A172 cells and U87 cells, and cell proliferation and invasiveness were obviously weakened. In response to the inhibition of β-catenin signaling, β-catenin/TCF4 transcriptional activity and STAT3 luciferase activity was strongly inhibited, as well as a greater decrease of mRNA and protein expression levels of β-catenin, TCF4, pAKT and pSTAT3.Similar results were also observed in vivo, intratumoral injection of PLGA-A-T microsphere significantly downregulated expression of β-catenin, TCF4, pAKT, pSTAT3 and PCNA, and also delayed tumor growth in nude mice harboring subcutaneous U87 xenografts. These results indicated that the synergistic cytotoxic effect of aspirin and temozolomide was achieved by aspirin- temozolomide -loaded PLGA nanoparticles through inhibition of β-catenin transactivation, offering the potential for improved treatment of glioblastomas.
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 776. doi:1538-7445.AM2012-776
Abstract 778: HER2 as therapeutic target for overcoming ATP-binding cassette transporter-mediated chemoresistance in small cell lung cancer
Authors: Minami Toshiyuki , Kijima Takashi , Otani Yasushi , Kohmo Satoshi , Takahashi Ryo , Nagatomo Izumi , Hirata Haruhiko , Suzuki Mayumi , Inoue Koji , Takeda Yoshito , Kida Hiroshi , Tachibana Isao , Kumanogoh Atsushi 
Published: August 2012

Abstract
Small Cell Lung Cancer (SCLC) easily acquires multidrug resistance after successful initial therapy. Overexpression of ATP-binding cassette (ABC) transporters is important for the multidrug resistance. Among them, ABCB1 and ABCG2 are known to be upregulated in chemoresistant SCLC. We found that human epidermal growth factor receptor 2 (HER2) expression is also upregulated in chemoresistant SBC-3/ETP, SBC-3/SN-38 and SBC-3/CDDP cells, compared to chemosensitive SBC-3 cells. Lapatinib, a tyrosine kinase inhibitor of HER2, could not suppress proliferation of these HER2-positive SCLC cells, but successfully restored chemosensitivity to etoposide and SN-38 in SBC-3/ETP and SBC-3/SN-38 cells, respectively. The reversal effect of lapatinib was thought to be caused by inhibition of drug efflux-pump functions of ABC transporters, and was producible with a clinically applicable concentration. Moreover, knocking down of HER2 by a small interfering RNA weakened the effect of lapatinib on ABCB1, indicating the involvement of HER2 in the inhibitory mechanisms. Notably, we demonstrated that caveolin-1 and Src play key roles in modulating ABCB1 function via HER2 inactivation. In SBC-3/ETP cells, dephosphorylation of HER2 by lapatinib activates Src and successively leads to increase caveolin-1 phosphorylation. Through this process, caveolin-1 dissociates from HER2 and strengthens association with ABCB1, and finally impairs the pump functions. Furthermore, we demonstrated that treatment by lapatinib in combination with etoposide or irinotecan significantly suppresses the growth of subcutaneous SBC-3/ETP and SBC-3/SN-38 tumors in mice, respectively. Collectively, these results indicate that combination therapy with lapatinib and cytotoxic agents could conquer ABC transporter-mediated chemoresistance in SCLC, especially in HER2-positive cases.
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 778. doi:1538-7445.AM2012-778
Abstract 780: An EGFR inhibitor enhances the efficacy of SN38, an active metabolite of irinotecan, in SN38-refractory gastric carcinoma cells
Authors: Yashiro Masakazu , Qiu Hong , Hasegawa Tsuyoshi , Zhang Xiaotian , Morisaki Tamami , Fukuoka Tatsuynari , Aomatsu Naoki , Hirakawa Toshiki , Sakurai Katsunobu , Kubo Naoshi , Tanaka Hiroaki , Yamada Nobuya , Maeda Kiyoshi , Sawada Tetsuji , Ohira Masaichi , Hirakawa Kosei 
Published: August 2012

Abstract
Background: Acquired drug resistance to irinotecan is one of the significant obstacles in the treatment of advanced gastric cancer. This study was performed to clarify the effect of epidermal growth factor receptor (EGFR) inhibitors in combination with SN38, an active metabolite of irinotecan, on the proliferation of irinotecan-refractory gastric cancer. Methods: Two irinotecan-resistant gastric cancer cell lines, OCUM-2M/SN38 and OCUM-8/SN38, were respectively established by stepwise exposure to SN38 from the parent gastric cancer cell lines OCUM-2M and OCUM-8. The combination effects of two EGFR inhibitors, gefitinib and lapatinib, with SN38 on proliferation, apoptosis, and cell-cycle on gastric cancer cells were examined. Results: Gefitinib or lapatinib showed synergistic anti-tumor effects against OCUM-2M/SN38 and OCUM-8/SN38 cells when used in combination with SN38, but not against OCUM-2M or OCUM-8 cells. SN38 increased the expression of EGFR and HER2 in OCUM-2M/SN38 and OCUM-8/SN38 cells. The combination of an EGFR inhibitor and SN38 significantly increased the levels of apoptosis-related molecules, caspase-6, p53, and DAPK-2, and resulted in the induction of apoptosis of irinotecan-resistant cells. The EGFR inhibitors increased the S-phase and decreased the UGT1A1 and ABCG expression in irinotecan-resistant cells. The SN38 plus Lapatinib group more effectively suppressed in vivo tumor growth by OCUM-2M/SN38 cells than either alone group.Conclusion: The combination treatment with an EGFR inhibitor and irinotecan might produce synergistic anti-tumor effects for irinotecan-refractory gastric cancer cells. The regulation of SN38 metabolism-related genes and cell cycle by EGFR inhibitors might be responsible for the synergism.

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 780. doi:1538-7445.AM2012-780
Abstract 781: The effect of vorinostat on the development of resistance to doxorubicin in neuroblastoma
Authors: Lautz Timothy B. , Jie Chunfa , Clark Sandra , Naiditch Jessica A , Jafari Nadereh , Qiu Yi-Yong , Zheng Xin , Madonna Mary Beth , Chu Fei 
Published: August 2012

Abstract
Histone deacetylase (HDAC) inhibitors, especially vorinostat, are currently under investigation as potential adjuncts in the treatment of neuroblastoma. The effect of vorinostat co-treatment on the development of resistance to other chemotherapeutic agents is unknown. In the present study, we treated two human neuroblastoma cell lines [SK-N-SH and SK-N-Be(2)C] with progressively increasing doses of doxorubicin under two conditions: with and without vorinsotat co-therapy. The resultant doxorubicin-resistant (DoxR) and vorinostat-treated doxorubicin resistant (DoxR-v) cells were equally resistant to doxorubicin despite significantly lower P-glycoprotein expression in the DoxR-v cells. Whole genome analysis was performed using the Ilumina Human HT-12 v4 Expression Beadchip to identify genes with differential expression unique to the DoxR-v cells. We uncovered a number of genes whose differential expression in the DoxR-v cells might contribute to their resistant phenotype, including hypoxia inducible factor-2. Finally, we used Gene Ontology to categorize the biological functions of the differentially expressed genes unique to the DoxR-v cells and found that genes involved in cellular metabolism were especially affected.
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 781. doi:1538-7445.AM2012-781
Abstract 782: Development of folate receptor positive drug-resistant cell lines and strategies to overcome drug resistance
Authors: Reddy Joseph A. , Dorton Ryan , Bloomfield Alicia , Nelson Melissa , Leamon Christopher 
Published: August 2012

Abstract
In support of our clinical strategy to treat folate receptor (FR)-positive platinum resistant ovarian cancer patients with the folate desacetylvinblastine (DAVLBH) conjugate, EC145, we created two FR-expressing DAVLBH resistant cell lines (named KB-DR and NCI/ADR-FR). Results from a calcein efflux assay confirmed that the KB-DR and NCI/ADR-FR cell lines both express high levels of an efflux pump, and subsequent flow cytometry analysis using an anti-p-glycoprotein (pgp) antibody (MRK-16) confirmed pgp overexpression. As predicted, these DAVLBH-resistant cell lines were also less sensitive to single agent EC145. However, when tested in combination with known pgp inhibitors, such as lapatinib or verapamil, substantially enhanced cell killing activity was observed. Furthermore, folate conjugates of non-pgp substrates, such as folate-tubulysin and a folate-epothilone, were also found to be highly active against these drug-resistant cell lines. In subsequent studies, we created a cisplatin resistant cell line (named KB-CR) and found that it remained just as susceptible to EC145 as the parent KB cells, suggesting that cisplatin-resistance did not affect FR function or sensitivity to folate-targeted microtubule inhibitors. Since the development of drug resistance did not appear to alter the function or exploitability of the FR, these new models will be useful for testing novel folate-targeted strategies for the treatment of difficult-to-treat 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 782. doi:1538-7445.AM2012-782
Abstract 793: Evolutionary therapy modeling for multidrug resistance: A novel concept of false drug
Authors: Kam Yoonseok , Khin Zayar , Gatenby Robert A. 
Published: August 2012

Abstract
The emergence of drug resistance is almost inevitably encountered during systematic cancer therapies resulting in treatment failure and tumor progression. The multidrug resistance (MDR), mediated by xenobiotic metabolism, is among the most well-known and well-studied mechanisms for drug resistance. Although MDR emergence is an evolutionary process, cancer therapies rarely incorporate evolutionary dynamics into their design. Here we present a study to develop a cancer treatment strategy targeting the metabolic cost of MDR and its evolutionary consequence. Through a new therapeutic strategy that reduces the fitness and proliferation of resistant cells by forcing them to use excess energy, we expect to stabilize the tumor volume by maintaining a constant population of sensitive cells and suppressing emergence of resistance. P-glycoprotein (PGP) is the best-known multidrug transporter responsible for MDR and lowers the intracellular drug concentration by an active drug export. A doxorubicin-resistant cell line MCF-7/dox showed significant overexpression of PGP pump when compared to MCF-7/wt, the parental drug-sensitive cell line. We focused on the metabolic energy cost due to the overexpression of the pump protein and its activity which requires about 2 ATP for each molecule of drug extruded. We hypothesized that the cost requires diversion of some resources which are, therefore, not available for proliferation thus reducing the evolutionary fitness of resistant cells. As expected, MCF-7/dox showed higher glycolytic activity and higher glucose demand for the growth and survival compared to the parental cell line MCF-7/wt. Due to the increased glucose consumption, MCF-7/dox appeared to be less competitive in a mixed culture with MCF-7/wt when the glucose resource was limited. We were able to increase the glycolytic activity further by applying other PGP substrates including verapamil at a non-cytotoxic dose. From these results, we propose a novel therapy using a “false drug,” which is not cytotoxic but nevertheless exported by PGP. The expenditure of resources required to extrude the false drug without any survival benefit is expected to further reduce the fitness of the MDR phenotype. When the mixed population was treated with verapamil at a non-lethal dosage, the drug-resistant population was significantly decreased further than when verapamil was not present. 2-deoxy glucose (2-DG), a glycolysis inhibitor, showed synergistic effect with verapamil in further reducing the MCF-7/dox population size.
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 793. doi:1538-7445.AM2012-793
Abstract 797: Gemcitabine resistant pancreatic cancer cell lines acquire an invasive phenotype with characteristics of EMT
Authors: Samulitis Betty , Wisner Lee , Dorr Robert , Landowski Terry H. 
Published: August 2012

Abstract
Gemcitabine is currently the standard first line treatment for patients with pancreatic cancer, however overall survival remains poor, and few options are available for patients that fail gemcitabine therapy. To identify potential molecular targets in gemcitabine refractory pancreatic cancer, we have developed gemcitabine resistant cell lines. Resistant cells were obtained by continuous exposure of MiaPaCa2 (MP) cells with increasing concentrations of gemcitabine. Stable cell lines were obtained with up to 500-fold resistance to gemcitabine. Characterization of the drug resistance cell lines has demonstrated no significant changes in gemcitabine uptake or metabolic pathways. The growth rate and doubling time of the drug resistant cell line is very similar to the parental drug sensitive cells with only small differences in response to gemcitabine. Cross resistance profiles demonstrate approximately 100-fold cross resistance to pyrimidine nucleoside cytarabine, but no resistance to the same in class agents, azacytidine and decitabine. Similarly, the gemcitabine resistant (GR) cell line displays 20-fold and 10-fold cross resistance to the purine nucleosides clofarabine and cladribine, respectively, but no differential response to fludarabine. Cell morphology of the drug resistant cells demonstrates characteristics of an epithelial-mesenchymal transition (EMT). Similarly, the GR cells are 5-fold more invasive in matrigel assays in vitro, and are significantly more aggressive in vivo. Microarray analysis demonstrated induced expression of several signaling pathways associated with EMT, including c-kit, TGFβ, and the JAG1/Notch axis. These data suggest that the primary mechanism of gemcitabine resistance is not related to alterations in drug uptake or metabolism, rather, the phenotype may reflect the selection of an intrinsic mechanism of enhanced cell survival. They further support a relationship between chemoresistance and EMT, and provide evidence for molecular pathways that may emerge as therapeutic targets in refractory pancreatic cancer.
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 797. doi:1538-7445.AM2012-797