bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3571: The Thioredoxin Reductase Inhibitor Chaetocin has Potent Antineoplastic Effects in Solid Tumors
Authors: Isham Crescent R. , Tibodeau Jennifer D. , Merchan Jaime R. , Bible Keith Christopher 
Published: February 2011

Abstract
Background: We had previously reported that the natural product chaetocin has potent and selective in vitro, ex vivo and in vivo anti-myeloma activity attributable to the imposition of cellular oxidative stress (ROS) in part mediated via competitive inhibition of the redox enzyme thioredoxin reductase. Having also observed chaetocin-induced cytotoxicity in solid tumor cell lines, we now extend prior work to characterize the effects of chaetocin in solid tumor cell lines and in human umbilical vein endothelial cells (HUVECs). Methods: The effects of chaetocin in solid tumor cell lines were assessed using colony forming assays, trypan blue exclusion assays, apoptosis and autophagy assays, electron microscopy, transcriptional profiling, and the National Cancer Institute 60 cell line screen. Results: Chaetocin demonstrated potent anti-cancer activity in all assessed solid tumor cell lines with IC50 values between 2-10 nM (24 h exposures, colony forming assays). While apoptosis was induced in a cell line-dependant fashion, it was not required for chaetocin-induced cytotoxicity, as ZVAD-fmk prevented apoptosis but not cell death. Markers of autophagy were not altered by chaetocin treatment. Interestingly, results form the NCI 60 cell line screen showed that hematological cell lines were generally more resistant to chaetocin than solid tumor lines despite our prior report indicating the activity of chaetocin in myeloma. Transcriptional profiling results were consistent with those anticipated from an agent producing cell death via imposition of cellular ROS, with heme oxidase-1 prominently induced along with other transcripts in pathways related to inflammatory response and cell death. Results from OxyBlot protein oxidation kit analyses (Millipore, Billerica, MA) confirmed a generalized increase in the carbonyl modification of proteins, a hallmark of cellular oxidative damage, in response to chaetocin treatment. Experiments using Rho0 mitochondrial inactive cells indicated that cellular ROS is induced by chaetocin independent of respiratory functional mitochondria. Chaetocin was also shown to block the interleukin-, fibroblast growth factor- or EGM2 media-induced proliferation of HUVEC cells at low-nanomolar concentrations. Conclusions: Chaetocin has wide-ranging antineoplastic activity across not only hematological, but also solid tumor, cell lines and displays evidence of antiangiogentic activity in HUVEC proliferation assays. Overall, chaetocin appears to be an attractive agent for further development as a candidate anti-cancer therapeutic in a variety of neoplasms. Supported in part by CA125750.
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 3571.
Abstract 3585: Taqman genotyping assays can be used on decalcified and paraffin embedded tissue from patients with osteosarcoma
Authors: Hagleitner Melanie M. , Coenen Marieke J.H. , Jeuken Judith W.M. , Flucke Uta , Schreuder Bart H.W. , Loo Maroeska D.W.M. te , Hoogerbrugge Peter M. 
Published: February 2011

Abstract
Insight in genetic variants predicting treatment outcome and/or side effects related to cancer medication will contribute to optimize treatment for the individual patients. However, most clinical trials performed so far in cancer treatment did not routinely collect and store patient germ line DNA. Formalin-fixed paraffin-embedded tissues (FFPE) from archived clinical samples could provide a source of germ line DNA for genetic research. Specially, in cancers like osteosarcoma with a 5-year overall survival of approximately 50-60%, archived histological specimens are often the only accessible source of biological material. This material, however, generally has been decalcified and paraffin-embedded for many years. DNA from formalin-fixed and paraffin embedded (FFPE) tissues, specially, in decalcified FFPE tissues has a higher frequency of non-reproducible sequence alterations compared with germ line DNA. In our study, we investigated whether DNA obtained from these tissues can be used for reliable single nucleotide polymorphism (SNP) genotyping. Therefore, we analyzed whether the genotypes obtained from DNA of these preserved tissues, were similar as those found in freshly DNA isolated from peripheral blood cells from the same patients. We studied two SNPs in the drug transporter MDR1 (ABCB1) using Taqman® SNP genotyping assays. Genotypes of the germ line DNA derived from freshly isolated DNA of 20 surviving patients with osteosarcoma were compared with genotypes obtained from archived material from decalcified FFPE blocks of the same patients. Decalcified FFPE-derived DNA yielded smaller PCR fragments compared to DNA extracted from peripheral blood cells, with a maximum reliable size of ∼300bp. We were able to evaluate each SNP in 19 of the 20 cases included in this study. All successfully genotyped samples showed 100%-concordance between genotypes obtained from DNA of FFPE tissue and the genotypes obtained from DNA of blood. In conclusion, we have demonstrated that decalcified FFPE tissue can be used for genetic polymorphism analysis using Taqman® allelic discrimination assays. This forms an unique opportunity to combine new insights in genetic research with historical patient cohorts, for instance of patients with osteosarcoma.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
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 3585.
Abstract 3589: Characterization of 17-dihydroexemestane glucuronidation. A role for the UGT2B17 deletion in exemestane pharmacogenetics
Authors: Sun Dongxiao , Chen Gang , Dellinger Ryan W. , Sharma Arun K. , Lazarus Philip 
Published: February 2011

Abstract
Exemestane is a 3rd-generation aromatase inhibitor (AI) used in the treatment of breast cancer in postmenopausal women. Reduction to form 17-dihydroexemestane and subsequent glucuronidation to hydroexemestane-17-O-glucuronide is a major pathway for exemestane metabolism. In the present study, homogenates from a newly-developed HEK293 aromatase-overexpressing cell line (HEK293-aro) were used to examine the activity of exemestane versus 17-dihydroexemestane in vitro. 17-dihydroexemestane exhibited an inhibition of estrone formation in HEK293-aro cell homogenates (IC50=2.3±0.83 μM) that was similar to that observed for exemestane (IC50=1.4±0.42 μM). UGT-overexpressing cell lines were screened for activity against 17-dihydroexemestane and UGTs 2B17&gt;1A10&gt;1A8&gt;1A4 were the only UGTs that exhibited activity. Of the hepatic UGTs, UGT2B17 exhibited a 17-fold higher Vmax/KM than UGT1A4. In human liver microsome (HLM) specimens, the rate of hydroexemestane-17-O-glucuronide formation using 17-dihydroexemestane as substrate was shown to be significantly (p&lt;0.001) decreased (14-fold) in HLMs from subjects with the UGT2B17 (0/0) deletion genotype as compared with HLMs from subjects wild type (+/+) for UGT2B17. A significant (r2=0.72) correlation was observed between HLM hydroexemestane-17-O-glucuronide formation and liver UGT2B17 expression in the same subjects, and the KM for UGT2B17(+/+) HLMs against 17-dihydroexemestane was 7.3 μM, ∼ 2-fold lower than that observed for UGT2B17 against 17-dihydroexemestane in vitro (14.5 μM). UGT2B17 (0/0) HLMs exhibited a 1.7-fold higher KM and a 36-fold lower Vmax/KM than UGT2B17
(+/+) HLMs. These data suggest that UGT2B17 is important in the metabolism of 17-dihydroexemestane, a major active metabolite of exemestane, and that the UGT2B17 deletion could have an important role in overall patient response to exemestane.
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 3589.
Abstract 3591: Efficacy and distribution of intratumoral paclitaxel given alone or in combination with doxorubicin using hydrogel in nude mice
Authors: Lee Joo-Ho , Kim Kwang-Suck , Kim Soo-Yeon , Kim Yu Jin , Al-abd Ahmed M. , Hong Ki-Yun , Song Soo-Chang , Kuh Hyo-Jeong 
Published: February 2011

Abstract
Intralesional chemotherapy is suggested to improve local tumor control as well as systemic toxicity profile of antitumor agents against solid tumors. Thermosensitive poly-(organophosphazene) hydrogel is a novel injectable polymer that transforms from sol to gel at body temperature. In this study, we evaluated distribution and efficacy of paclitaxel (PTX) when given as intratumoral injection using the hydrogel or solution formulation in human SNU-601 tumor xenograft-bearing nude mice. Following intratumoral injection of 60 mg/kg of PTX, plasma drug concentrations were lower than 0.5 μg/ml(LOQ) for both hydrogel and solution. For PTX tumor concentration, Cmax was 1.2 folds higher and T1/2 3.7 folds longer with hydrogel compared to solution. Over 21d, AUCtumor was 1.5 folds greater in hydrogel compared to solution, indicating greater drug exposure and retention at target site. The antitumor activity of PTX (30 mg/kg) when given alone or in combination with doxorubicin (DOX, 15 mg/kg) was evaluated after intratumoral hydrogel injection in SNU-601 (Td= 21 d) and SNU-398 (Td= 5 d) xenograft models. The synergism between DOX and PTX, independent of dosage form, was observed in SNU-398, but not in SNU-601. No toxicity was observed in hydrogel group in neither single nor combination treatment. For slow-growing SNU-601 tumor, combination of PTX and DOX given in hyrogel mixture showed greater activity than that of solution. In conclusion, poly-(organophosphazene) polymer may be useful in intralesional administration of PTX to achieve greater drug exposure at target site. Also, combination of DOX and PTX, showed a potential for greater antitumor efficacy, which warrants further evaluation.
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 3591.
Abstract 3597: Association between the ABCG2 polymorphisms and the gefitinib-induced side effects in Japanese patients with non-small cell lung cancer
Authors: Imai Yasuo , Akasaka Keiichi , Kaburagi Takayuki , Imura Johji , Ueda Yoshihiko 
Published: February 2011

Abstract
ABCG2 is a half-size ATP-binding cassette transporter implicated in cellular gefitinib transport. Reportedly, the c.421C&gt;A ABCG2 gene variant was associated with gefitinib-induced diarrhea in Caucasian patients with non-small cell lung cancer. c.421C&gt;A ABCG2, resulting in p.Q141K substitution, is more prevalent in Asian populations. Therefore, the putative relationship between gefitinib-induced adverse effects and this functional polymorphism was investigated in 75 Japanese patients with non-small cell lung cancer treated with gefitinib 250 mg/d orally, and the results were correlated with treatment-related adverse effects. c.376 C&gt;T, resulting in truncated, non-functional ABCG2, was also investigated. Forty one (54.7%) patients harbored 376T or 421A ABCG2 on at least one allele, while the remaining 34 (45.3%) were wild type for ABCG2. No significant group differences were observed in frequency of gefitinib-related diarrhea or other adverse effects. Next, DLD-1 colon cancer cells expressing wild-type (DLD-1/WT) or 141K mutant ABCG2 (DLD-1/Q141K) were established for investigation of in-vitro cell sensitivity to the ABCG2-substrate drugs, gefitinib and SN-38. ABCG2 expression was much lower in DLD-1/Q141K cells than in DLD-1/WT cells, despite similar ABCG2 mRNA levels. DLD-1/WT cells acquired more resistance to SN-38 than did DLD-1/Q141K cells, but neither cell line acquired gefitinib resistance compared with parental cells. In-vitro data also suggested that ABCG2 has only a limited role in toxicity of gefitinib, but not SN-38, in colon-derived cells.
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 3597.
Abstract 3630: In vitro and in vivo antitumor activity of multi-tyrosine Kinase inhibitors in neuroblastoma
Authors: Calero Raul , Serrano Rosario , Avendaño Laura , Poblet Enrique , Ocana Alberto 
Published: February 2011

Abstract
Background: Despite Neuroblastoma (NB) is a curable tumor in its early stages, high risk patients continue to have a bad prognosis and a poor survival. Tyrosine kinase receptors mediate proliferation and survival and have been associated with oncogenic transformation in many human tumour types including NB. Sorafenib and sunitinib are two multityrosine kinase inhibitors that have shown antitumor activity in some solid tumours, like renal cell carcinoma. Evaluation of approved multi TK inhibitors in NB is a main goal in order to identify novel therapeutic options of treatment.
Methods: Here, we tested the antitumor activity of sorafenib and sunitinib, two multityrosine kinase inhibitors, in NB cell lines and in an animal model. To this end, we have used cancer cell lines and an in vivo xenografted mouse model. MTT proliferation, apoptosis assays, immunohistochemical analysis, and biochemical experiments were performed to investigate the molecular bases of the action of both compounds, of sunitinib alone, or of sunitinib in combination with standard chemotherapy.
Results: Using a representative panel of NB cell lines, we report that sunitinib exhibits a potent antitumor activity in vitro (IC50 0.8-2.6 µM) and a better growth inhibition profile compared with sorafenib (IC50 0.5-5.2 µM). Sunitinib also shows a high therapeutic index, when tested in non-transformed cells, and is synergic at very low doses (0.1 µM) with chemotherapies used for the treatment of NB tumors. Mechanistically sunitinib inhibits several tyrosine kinase receptor proteins and the downstream PI3-AKT pathway. Administration of sunitinib to NB cells induces cell cycle arrest and stimulates apoptosis. In vivo xenograft studies revealed a significant antitumor activity of sunitinib compared with the control group in two types of cell lines (SH-SY5Y, P=0.02 and SK-N-BE, P=0.08). Sunitinib demonstrated an anti-angiogenic effect in vivo with a reduction of markers associated with angiogenesis (e.g. factor VIII).
Conclusion: These results demonstrate the antitumor activity of sunitinib in NB tumors and support their further development in clinical studies alone or in combination with chemotherapy.
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 3630.
Abstract 3635: Novel chemotherapeutic agent AN019 for lapatinib-resistant breast cancer
Authors: Gondi Christopher S. , Gorantla Bharathi , Rao A.K.S. Bhujanga , Amala K. , Naidu M.U.R. , Jogi K.V. , Ramana G.V. , Chowdary M. Praveen , Rao Jasti S. 
Published: February 2011

Abstract
Breast cancer is the most frequently diagnosed cancer in women. Overexpression of human epidermal growth factor receptors (EGFRs) represents a biological subclass of breast cancer with distinct molecular alterations, clinical behavior, and response to systemic therapy. In this study, we introduce a novel compound (AN019) that has greater anti-tumor activity than Lapatinib. We demonstrate that AN019 is more effective at inhibiting the angiogenic potential and proliferation of both MDAMB231 and HTB20/BT474 cells. FACS analysis shows that AN019 treatment also caused the accumulation of MDAMB231 and HTB20/BT474 cells in the sub-G0/1 phase in a dose-dependent manner; this effect was accompanied by increased PARP cleavage indicative of apoptosis. Strong inhibition of EGFR phosphorylation was also observed in both MDAMB231 and HTB20/BT474 cells. HTB20/BT474 cells did not respond well to Lapatinib treatment when compared to AN019 treatment. From our animal studies using SCID mice implanted with HTB20/BT474 cells, we observed a dose-dependent inhibition of tumor growth when compared to controls or Lapatinib-treated mice at comparable concentrations. A dose-dependent inhibition of EGFR phosphorylation was also observed from immunohistochemical analysis of tumor sections. Our results show that AN019 is superior to Lapatinib in EGFR-overexpressing cells and has strong anti-angiogenic, anti-proliferative and pro-apoptotic properties. In vivo studies demonstrate the increased anti-tumor activity of AN019 over Lapatinib. These results suggest the therapeutic potential of AN019 as anti-angiogenic and anti-proliferative agent in Lapatinib-resistant and EGFR-overexpressing cells.
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 3635.
Abstract 3643: Manipulation of HuR expression alters the efficacy of PARP-inhibitors in pancreatic and ovarian cancer cells
Authors: Costantino Christina L. , Richards Nathan G. , Cozzitorto Joseph , Rittenhouse David , Gonye Greg , Yeo Charles J. , Witkiewicz Agnes , Brody Jonathan R. 
Published: February 2011

Abstract
PARP-inhibitors (PARPi) are a novel class of agents that target cancer cells deficient in DNA repair. Early phase trials show promising success with PARP-inhibitors, yet drug resistance mechanisms and off-target pathways affected by drug exposure have not been explored. HuR (ELAV1) is a protein that binds and stabilizes mRNA transcripts upon certain stress stimuli. These HuR mRNA targets result in an increase in protein expression; and thus, protein function. Recently, we demonstrated that HuR binds and regulates deoxycytidine kinase, the gemcitabine metabolizing enzyme. Thus, HuR expression enhances gemcitabine efficacy against pancreatic cancer cells. We subsequently screened other chemotherapeutics that may stimulate the HuR stress response. In isogenic pancreatic cancer cell lines, stable HuR overexpression rendered cells up to 2-fold more sensitive to PARPi compared to control cells. Accordingly, siRNA knock down of HuR expression in both pancreatic and ovarian cancer cell lines caused PARPi resistance compared to a scramble-sequence control siRNA. In a pancreatic cancer cell line, MiaPaCa2, a 2.5-fold siRNA knock down of HuR mRNA expression detected by qPCR rendered cells approximately 4-fold more resistant to PARPi. Similarly, a modest siRNA knock down of HuR in an ovarian cancer cell line, A2780, rendered cells more resistant to PARPi. Immunofluorescence studies indicate that a 5 hour treatment with 75 µM PARPi directly caused HuR to transport from the nucleus to the cytoplasm, presumably moving ARE-rich mRNA cargoes after drug exposure. Focused gene expression analysis on HuR bound, immunoprecipitated RNA defined functional HuR downstream targets (including deoxycytidine kinase). Current studies will reveal and validate the importance of these downstream mRNA targets in PARP-inhibitor metabolism and efficacy. We hypothesize that HuR may be central to PARPi effectiveness and may be useful in understanding PARPi de novo drug resistance mechanisms. Future work will reveal whether HuR status can be utilized as a predictive marker for PARP-inhibitor-based therapy and if all clinically available PARP-inhibitors engage HuR's regulation of unique mRNA cargoes in cancer cells upon treatment.
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 3643.
Abstract 3648: Proteomic profiling of vorinostat in breast cancer
Authors: Shaw Patrick G. , Chearkady Raghothama , Pandey Akhilesh , Davidson Nancy 
Published: February 2011

Abstract
The lysine deacetylase (KDAC) inhibitor, vorinostat or suberoylanilide hydroxamic acid (SAHA), is currently being used for treatment of cutaneous T cell lymphoma, however, its anti-breast cancer effects are under evaluation. SAHA's pluripotent effect on histone and non-histone lysine acetylation across cancer types raises the theoretical concern that it could both re-express epigenetically silenced tumor suppressors and activate oncogenic pathways as well. In order to investigate the potential role of SAHA in tumor suppressor, cell death and signaling pathways, we used quantitative mass spectrometric analysis of MCF10A normal mammary epithelial cells and MDA-MB-231 breast cancer cells treated with SAHA for 12 and 24 hours. We observed downregulation of EGFR, Ephrin type A receptors and cell cycle proteins including CDC2 and CDC42 protein kinase, which is consistent with anti-tumor activity. We found that SAHA treatment also promoted activation of proteins including Ephrin type B receptors, STAT3 and p120 Catenin. Such molecular effects must be characterized in greater detail in order to determine the potential efficacy of this drug in breast cancer. Our findings show that SAHA-mediated inhibition of KDACs results in a wide range of downstream consequences in mammary epithelial and breast cancer cells. Candidate molecules identified in this study can be used as biomarkers to assay the breast cancer response to SAHA.
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 3648.