bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5429: Cytotoxicity of AOH compounds targeting the interaction of caPCNA and its binding partners in human cancer cells
Authors: Shen Fei , Hickey Robert , Kamran Jasmine , Smith Shanna , Phipps Elizabeth , Malkas Linda 
Published: June 2012

Abstract
Previously we reported the identification of an acidic isoform of proliferating cell nuclear antigen (caPCNA) in various cancer cells. Proliferating Cell Nuclear Antigen (PCNA) interacts with multiple binding partners to carry out vital cellular processes including DNA replication, DNA damage repair, and cell-cycle progression. We hypothesize that caPCNA performs similar functions specifically in cancer cells and, therefore, disrupting interactions of caPCNA with its binding partners will prevent necessary cellular functions, resulting in cytotoxicity to cancer cells. AOH compounds were generated based on a focused computer molecular “docking” search for small molecules that specifically targeted the interaction of caPCNA and its binding partner FEN1. MTT assays suggest that several AOH compounds have promising anti-proliferation effects in human breast and pancreatic cancer cells with EC50 values as low as or less than 10uM (lead compounds). To further evaluate the cytotoxicity of lead AOH compounds, clonogenic survival assays were performed in MCF-7 cells treated with the small molecules for 2 hours. Results showed that AOH compounds induced cytotoxicity in cancer cells in a dose-dependent manner. The IC50s of these compounds were between 10 to 20uM in MCF-7cells. To investigate the effects of the AOH compounds on DNA replication and the cell cycle, in vitro SV40 DNA replication assays and flow cytometric analysis were performed. The G2/M phase cell population was increased from 8% to 30-80% in MCF-7 cells treated with 25uM AOH compounds for 48 hours, indicating an induction of G2 arrest. AOH compound at 10uM inhibited in vitro DNA replication in malignant cell extracts by 70-80% relative to untreated correspondent cell extracts. Taken together, the potent cytotoxicity of AOH compounds in cancer cells is correlated with their inhibition of DNA replication and induction of cell cycle arrest. The compounds may be useful in the future for clinical cancer chemotherapy as a single anticancer agent and/or in combination with other anti-neoplastic agents.
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 5429. doi:10.1158/1538-7445.AM2011-5429
Abstract 5432: Spirooxindole derivative (SOID-8) inhibits proliferation and induces apoptosis by blocking JAK2/STAT3 signaling in melanoma cells
Authors: Tian Yan , Nam Sangkil , Liu Lucy , Yakushijin Fumiko , Buettner Ralf , Liang Wei , Yang Fan , Horne David , Jove Richard 
Published: June 2012

Abstract
Melanoma is the most malignant skin cancer, and is generally refractory to current chemotherapy, so new treatment strategies are needed. In this study, we show that a spirooxindole derivative, SOID-8, which is a synthetic analogue inspired by the natural product, spirotryprostatin B, significantly inhibits cell proliferation in four established human melanoma cell lines. This decrease in viability of A2058 and A375 melanoma cells is associated with apoptosis, as confirmed by an increase in poly(ADP-ribose)polymerase cleavage. In addition, the antiapoptotic protein Mcl-1, a member of the Bcl-2 family, is downregulated and correlated with SOID-8 induced apoptosis. Morevoer, SOID-8 inhibits tyrosine phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) in both melanoma cell lines in a dose- and time-dependent manner. In contrast, phosphorylation of AKT (protein kinase B) is reduced by SOID-8 only at high concentrations, and phosphorylation of MAPK (extracellular signal-regulated kinase 1/2) is not inhibited at all by SOID-8 in these cells. Furthermore, this compound decreases the phosphorylated Janus kinase-2 (JAK2) levels in a dose- and time-dependent fashion. Importantly, SOID-8 inhibits phosphorylation of STAT3 and JAK2 induced by IL-6 stimulation in A2058 and A375 cells. In summary, our results show that SOID-8 selectively blocks JAK2/STAT3 signaling as well as expression of apoptosis regulatory proteins, associated with inhibition of cell proliferation and induction of apoptosis in melanoma cells. These data suggest that antitumor activity of the spirooxindole derivative SOID-8 is at least partially due to inhibition of JAK2/STAT3 signaling in melanoma cells and is a promising small molecule candidate for melanoma therapy.
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 5432. doi:10.1158/1538-7445.AM2011-5432
Abstract 5439: A novel drug sensitivity assay method for 3D cultured cell using an imaging device
Authors: Sakamoto Ruriko , Sakemura Noriko , Shimomura Manami , Hirakawa Noboru , Watanabe Hirotada , Tanaka Satoru , Yoshida Kaori , Nakatsura Tetsuya 
Published: June 2012

Abstract
Three-dimensional (3D) cultured cells are useful for the physiological study of tumor cells owing to their similar characteristics. Currently, the popular methods for 3D cell culture-for example, collagen gel or the matrix method-involve complicated procedures that often result in experimental errors. We attemted to develop a novel technique for the use of 3D cell culture in a novel drug sensitivity assay using an imaging technique. We used a NanoCulture® plate (NCP) for 3D cell culture of the human breast cancer cell lines BT474 and T47D for forming multicellular spheroids and used these in a drug sensitivity assay for trastuzumab and paclitaxel by employing the imaging device BioStation CT. The NCP has a fine pattern carved on the surface of the wells’ bottoms, which provides scaffolding for cells with expanding pseudopodia. Thus, the cells can move and aggregate to form uniform spheroids on the NCP. These spheroids further migrate and fuse each other during culture. The effects of anticancer drugs-i.e., a decrease in the migration velocity of spheroids and suppression of spheroid fusion in a dose-dependent manner-were estimated using NCP-cultures spheroids analyzed using sequential BioStation CT images. These results were compared to the conventional assay method of ATP quantification with a good agreement. We confirmed the antitumor effect of the drugs on cells seeded in a single well of the 96-well plate by this technique. We expect this method to be useful in research on new antitumor agents and in drug sensitivity tests for individually tailored cancer treatments.
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 5439. doi:10.1158/1538-7445.AM2011-5439
Abstract 5448: Pharmacogenetics of drug transporters may be useful to identify chronic myeloid leukemia patients who are less likely to achieve molecular responses to imatinib: Implications for treatment optimization in the era of new tyrosine kinase inhibitors
Authors: Soverini Simona , Angelini Sabrina , Barnett Matt , Ravegnini Gloria , Pane Fabrizio , Hughes Timothy P. , White Deborah , Kim Dong-Wook , Saglio Giuseppe , Rosti Gianantonio , Woodman Richard , Woodman Richard , Hrelia Patrizia , Biasco Guido , Baccarani Michele , Martinelli Giovanni 
Published: June 2012

Abstract
The availability of multiple options for chronic myeloid leukemia (CML) treatment is not paralleled by the availability of biological predictors of outcome allowing to identify patients (pts) who are more likely to benefit from dasatinib or nilotinib rather than imatinib (IM). We thus investigated a panel of 20 SNPs in ABCB1, ABCG2, SLC22A1, OCTN1, CYP3A4 and CYP3A5 genes that can be hypothesized to influence IM transport and metabolism in 189 newly diagnosed CML pts enrolled in the TOPS phase III trial (Cortes et al, J Clin Oncol 2010). Median age was 46 yrs; male to female ratio was 103:86; 156 (83%) pts were Caucasian and 23 (12%) were Asian; low, intermediate and high Sokal risk pts were 84 (44.4%), 65 (34.4%) and 40 (21.2%), respectively. Baseline demographic/clinical features did not differ significantly from those of the entire population enrolled. Treatment outcomes (major molecular response [MMR]; complete molecular response [CMR]) were compared according to i) each candidate genotype ii) summary measures based on combinations of SNPs in the same gene and iii) summary measures based on combinations of SNPs in functionally related genes (uptake; efflux). Additive models, with SNPs represented as number of major alleles, were used. Significant results are summarized in the Table below and will be presented in detail. Cumulative incidence plots were also analysed, with similar results. Our data suggest that in CML pts, genotyping should be taken into account in an attempt to further individualize treatment, with the aim of enhancing efficacy in terms of MMR and CMR achievement. On the basis of our findings, stratification of pts according to genotypes may be proposed for selection between IM and second generation TKIs, and represents an attractive opportunity for new clinical trials.
Supported by Novartis, TOPS Correlative Studies Network

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 5448. doi:10.1158/1538-7445.AM2011-5448
Abstract 5452: Functional genome-wide approach identifies genes associated with chemotherapeutic susceptibility in individuals of African descent
Authors: Wheeler Heather E. , Stark Amy L. , Gorsic Lidija K. , Gamazon Eric R. , Cox Nancy J. , Dolan M. Eileen 
Published: June 2012

Abstract
Chemotherapeutic agents are used in the treatment of many cancers, yet variable resistance and toxicities among individuals limit successful outcomes. Several studies have indicated outcome differences associated with ancestry among patients with various cancer types. We performed genome-wide association studies (GWAS) in lymphoblastoid cell lines derived from Yoruba (YRI; n = 176) and African American (ASW; n = 83) populations and identified SNP predictors of cellular susceptibility to cisplatin, carboplatin, capecitabine and ara-C. To account for population structure in African American population, we incorporated local ancestry information into our association model. We found that chemotherapeutic susceptibility SNPs in the YRI are enriched for expression quantitative trait loci (eQTLs, p&lt;10-3). Most of these are trans eQTLs and thus simply examining the region directly surrounding a SNP that associates with a phenotype of interest for possible functional genes is inadequate. Traditional GWAS that test single markers are powered to detect SNP associations with relatively strong effects, but are unable to detect multiple smaller effects working together. Using a novel functional gene-based genome-wide association approach, we identified 10, 13, and 1 suggestive candidate genes for association with cytarabine-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10-4) in ASW. Functional GWAS in the YRI resulted in the genome-wide significant association of 234 genes with cisplatin IC50, 81 genes with 5’-deoxyfluorouridine AUC, 64 genes with carboplatin IC50 and 13 genes with cytarabine AUC (p&lt;10-6). Our genome-wide SNP- and gene-based approaches that incorporate local ancestry information can be used to elucidate genes functionally contributing to a wide range of phenotypes in African American populations.
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 5452. doi:10.1158/1538-7445.AM2011-5452
Abstract 5456: Functional genomics reveals diverse cellular processes that modulate tumor cell response to oxaliplatin
Authors: Harradine Kelly , Kassner Michelle , Chow Donald , Aziz Meraj , Von Hoff Daniel D. , Baker Joffre , Yin Hongwei , Pelham Robert J. 
Published: June 2012

Abstract
Oxaliplatin is widely used to treat colorectal cancer, as both adjuvant therapy for resected disease and palliative treatment of metastatic disease. However, a significant number of patients experience serious side effects from oxaliplatin treatment, including prolonged neurotoxicity, creating an urgent need for biomarkers of oxaliplatin response or resistance to direct therapy to those most likely to benefit. As a first step to improve selection of patients for oxaliplatin-based chemotherapy, we have conducted an in vitro cell-based small interfering RNA (siRNA) screen of 500 genes aimed at identifying genes whose loss of expression alters tumor cell response to oxaliplatin. The siRNA screen identified twenty-seven genes, that when silenced, significantly altered colon tumor cell line sensitivity to oxaliplatin. Silencing of a group of putative resistance genes increased the extent of oxaliplatin-mediated DNA damage and inhibited cell cycle progression in oxaliplatin-treated cells. The activity of several signaling nodes, including AKT1 and MEK1, was also altered. We used cDNA transfection to over-express two genes (LTBR and TMEM30A) that were identified in the siRNA screen as mediators of oxaliplatin sensitivity. In both instances, over-expression conferred resistance to oxaliplatin. In summary, this study identifies numerous putative predictive biomarkers of response to oxaliplatin which should be studied further in patient specimens for potential clinical application. Diverse gene networks appear to influence tumor survival in response to DNA damage by oxaliplatin. Finally, those genes whose loss of expression (or function) is related to oxaliplatin sensitivity may be promising therapeutic targets to increase patient response to oxaliplatin.
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 5456. doi:10.1158/1538-7445.AM2011-5456
Abstract 5465: Modulation of DMS612 (BEN) pharmacokinetics and metabolism in mice by disulfiram, and aldehyde dehydrogenase inhibitor
Authors: Parise Robert A. , Beumer Jan , Clausen Dana , Egorin Merrill , Covey Joseph , Eiseman Julie 
Published: June 2012

Abstract
Introduction: DMS612 (NSC 281612, BEN) is an alkylating agent in clinical trials based on its in vitro and in vivo activity against renal cell carcinoma. We previously reported that BEN is rapidly metabolized into its carboxylic acid (BA), and that BEN and BA undergo chemical degradation both in vitro and in vivo. In addition, we demonstrated that BEN is rapidly metabolized into at least 13 different analytes in vivo. We hypothesized that BEN is metabolized to BA by aldehyde dehydrogenase (ALDH). In an attempt to increase the exposure to BEN, we explored the effect of the ALDH inhibitor disulfiram on the pharmacokinetics of BEN in mice.
Materials & Methods: Female CD2F1 mice were dosed with either 20 mg/kg BEN i.v. alone or 24 h after the i.p. administration of 300 mg/kg disulfiram. Plasma and urine concentrations of BEN and its metabolites were quantitated by LC-MS/MS. Plasma pharmacokinetic parameters were calculated non-compartmentally. Urinary excretion of BEN and metabolites was calculated as percentage of the dose.
Results: BEN was metabolized to at least 13 different products as previously reported. In the BEN alone study, BEN was metabolized quickly with a half-life &lt;5 min. The half-lives of the metabolites were &lt; 2 h. Pretreatment with disulfiram resulted in a 300-fold increase in exposure to BEN, from AUC0-inf 143 ng/mL*min to 40,515 ng/mL*min, while BA exposure remained similar, at AUC0-inf 254,280 ng/mL*min after BEN alone to AUC0-inf 274,947 ng/mL*min after disulfiram. In addition, the half-lives and AUCs of some of the metabolites in the BEN + disulfiram study appeared to be longer than when BEN was administered alone. Urinary excretion of BEN was increased 50% after disulfiram (from 1% to 1.5 % of the dose), BA excretion accounted for 5.8% of the dose after BEN alone and this was not markedly affected by disulfiram pretreatment.
Conclusions: BEN is rapidly metabolized into many metabolites, which could affect the efficacy of BEN as an anti-neoplastic agent. We have demonstrated that by administering the ALDH inhibitor disulfiram the exposure to BEN is greatly increased, suggesting that ALDH is at least partly responsible for the rapid metabolism of BEN. However, the plasma exposure to BA increased only 8%. Our results will aid in the interpretation of ongoing clinical studies with BEN, which include genotyping for ALDH.
Support: N01-CM07106, N01-CM52202, P30-CA47904.
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 5465. doi:10.1158/1538-7445.AM2011-5465
Abstract 5469: Pharmacokinetics and activity of nanoliposomal irinotecan (MM-398) against Ewings Sarcoma xenografts are superior to the conventional irinotecan formulation
Authors: Wang Jing , Zhuo Rupeng , Drummond Daryl , Reynolds C. Patrick , Kang Min H. 
Published: June 2012

Abstract
Background: Irinotecan (CPT-11) is an antineoplastic prodrug, of which SN-38 is an active metabolite. Liposomal CPT-11 was developed to improve systemic and tumor exposure to CPT-11 and its active metabolite by reducing the exposure of CPT-11 to neutral and basic pH, in which CPT-11 is hydrolyzed into an inactive carboxylate form. The aims of the current study are 1) to compare the plasma and tissue/tumor pharmacokinetics of nanoliposomal CPT-11 (in clinical trials as PEP02 or MM-398) and conventional irinotecan in mice, and 2) to compare anti-tumor activity of the two formulations against Ewings Sarcoma murine xenografts. Methods: An assay using liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed to measure CPT-11 and SN-38 concentrations in plasma and tissue. Plasma and tissue pharmacokinetics of liposomal and conventional irinotecan were characterized in Balb/c mice (non-tumor bearing); pharmacokinetics and activity were assessed in athymic nu/nu mice xenografted with human Ewings sarcoma. Results: Following a 20 mg/kg dose of intravenous liposomal irinotecan, both plasma and tumor concentrations of CPT-11 and SN-38 were approximately 10-fold higher than conventional irinotecan. The Cmax and AUC were dose-proportionally increased after a single dose of liposomal irinotecan in non-tumor bearing mice. In mice xenografted with Ewings sarcoma (CHLA-258), liposomal irinotecan significantly extended event-free survival of mice compared with controls or conventional irinotecan (P&lt;0.05). Conclusions: Our data demonstrate that 1) liposomal CPT-11 achieves higher plasma and tissue concentrations with longer duration compared with conventional irinotecan, and that 2) liposomal formulation has greater anti-tumor activity relative to conventional irinotecan. These results suggest that liposomal irinotecan may provide improved anti-tumor activity over conventional irinotecan by increasing systemic and tumor exposures to the SN-38 active metabolite.
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 5469. doi:10.1158/1538-7445.AM2011-5469
Abstract 5492: Preclinical study of the PARP inhibitor ABT-888 in metastatic prostate cancer
Authors: Zhang Jingsong , Mcgregor Natalie , Hussain Maha H. , Chinnaiyan Arul 
Published: June 2012

Abstract
Background: Despite recent advances in androgen deprivation therapy, chemotherapy and immunotherapy, metastatic prostate cancers (mPCa) eventually become resistant to these treatments through further mutations. Cancer cells often diminish their DNA repair pathways to obtain high mutation rates. We aimed to develop a therapeutic approach that directly targets cells with high mutation rates and explored the therapeutic potential of PARP inhibitor, ABT-888 (kindly provided by Abbott) in mPCa preclinical models. Methods and Results: Meta-analysis of 5 published prostate cancer gene expression profiles with total of 53 metastatic samples and 183 primary samples were performed with oncomine 4.1. BRCA1 was among genes significantly over expressed in mPCa. Inhibiting BRCA1 expression with shRNA in Lncap (intact PTEN) and PC3 (loss of PTEN) cells, however, did not lead to synthetic lethality when ABT-888 (up to 10uM) were added in the in vitro cytotoxicity assays. When ABT-888 was combined with DNA damaging chemotherapy agents, synergies in cell killing were observed with 100nM of ABT-888 and 10nM SN38, an active metabolite of topoisomerase I inhibitor CPT-11. Such synergies were observed at higher dose levels with Temazolomide (1uM) and ABT-888 (1uM). The enhanced cell killing correlated well with inhibition of PAR and increased formation of DNA double strand breaks. No synergies with ABT888 were observed with topoisomerase II inhibitor (etoposide and mitoxantrone) or platinums in the WST-1 cytotoxicity assays. The CPT-11 and ABT888 combination was then tested in PC3 mouse xenografts with 4 treatment groups: vehicle control, ABT-888, CPT-11, and ABT-888 plus CPT-11. ABT-888 was given by oral gavages at 12.5mg/kg on days 1-5 of each 21 day cycle; whereas CPT-11 was given by intraperitoneal injection at 60mg/kg on days 1 and 5 of each 21 day cycle. Compared to vehicle control, ABT-888 by itself had no anti-tumor activities. The inhibition of tumor growth by CPT-11 was further enhanced when it was combined with ABT-888. More than 30% tumor volume shrinkage was observed in 4 of the 8 xenografts after 2 cycles of treatments with ABT-888 and CPT-11. These anti-tumor effects, however, were not sustainable beyond treatment cycles. Conclusion: ABT-888 enhanced the anti-tumor activities of CPT-11. The dose and schedule of this combination will be modified and its anti-tumor activities will be compared with docetaxel in future pre-clinical studies.
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 5492. doi:10.1158/1538-7445.AM2011-5492