bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2454: High susceptibility to azoxymethane-induced ear duct and intestinal carcinogenesis in diabetic OLETF rats
Authors: Izumi Keisuke , Hafez Ezar , Takahashi Tetsuyuki , Ogawa Hirohisa 
Published: February 2011

Abstract
Diabetes and obesity are thought to be risk factors for colorectal cancer in humans. In our recent study, whole body X-irradiated Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model animal of type 2 diabetes, developed low incidence of small intestine adenocarcinoma, but not in nondiabetic Long-Evans Tokushima Otsuka (LETO) rats. In the present study, six-week-old male OLETF and LETO rats (n=24) were given weekly s.c. injections of 15 mg/kg azoxymethane (AOM) for three weeks and killed after 30 weeks from the initial treatment. The incidences of ear duct tumors in LETO and OLETF rats were 0% and 67% (P&lt;0.001), respectively. Those of small intestine tumors in these strains were 0% and 43% (P&lt;0.001), respectively, and those of colon tumors were 46% and 79% (P&lt;0.05), respectively. Serum triglyceride and free fatty acid levels in OLETF rats were significantly higher than those in LETO rats at sacrifice, but average serum insulin was lower than that in LETO rats. Fatty change of hepatocytes was common in OLETF rats, but not in LETO rats. Hepatic IGF-1, leptin and PAI-1 mRNA levels were not different in two strains. These data suggest that hyperlipidemia plays an important role in high susceptibility to AOM-induced carcinogenesis in OLETF rats.
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 2454.
Abstract 2459: Early changes in gene expression induced by tobacco smoke: Evidence for the importance of estrogen within lung tissue
Authors: Meireles Sibele I. , Esteves Gustavo H. , Hirata Roberto , Peri Suraj , Devarajan Karthik , Slifker Michael , Mosier Stacy L. , Vadhanam Manicka V. , Hurst Harrell E. , Neves E. Jordao , Reis Luiz F. L. , Gairola C. Gary , Gupta Ramesh C. , Clapper Margie L. 
Published: February 2011

Abstract
Lung cancer is the leading cause of cancer deaths in the U.S., surpassing breast cancer as the primary cause of cancer-related mortality in women. The goal of the present study was to identify early molecular changes in the lung induced by exposure to tobacco smoke and thus identify potential targets for chemoprevention. Female A/J mice were exposed to either tobacco smoke or HEPA-filtered air via a whole-body exposure chamber (6 h/day; 5 days/wk for 3, 8 and 20 wk). Gene expression profiles of lung tissue from control and smoke-exposed animals were established using a 15 K cDNA microarray. Cytochrome P450 1b1 (Cyp1b1), a Phase I enzyme involved in both the metabolism of xenobiotics and the 4-hydroxylation of 17β estradiol, was modulated to the greatest extent following smoke exposure. A panel of 10 genes were found to be differentially expressed between control and smoke-exposed animals at 3, 8 and 20 wk (P &lt; 0.001). The interaction network of these differentially expressed genes revealed new pathways modulated by short-term smoke exposure including estrogen metabolism. In addition, 17β-estradiol was detected within murine lung tissue by gas chromatography coupled mass spectroscopy and immunohistochemistry. Identification of the early molecular events that contribute to lung tumor formation is anticipated to lead to the development of promising targeted chemopreventive therapies. In conclusion, the presence of 17β-estradiol within lung tissue when combined with the modulation of Cyp1b1 and other estrogen metabolism genes by tobacco smoke provides novel insight into a possible role for estrogens in lung cancer. (Supported by fellowships from the AACR-Pennsylvania Department of Health and the ASPO/CRPF, the Estate of Jane Villon, the Jerome M. Spencer and Arnold Zaslow Family Foundation and NIH CA-96310).
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 2459.
Abstract 2461: Gene deletion of mPGES-1 results in a significant reduction in tumor stage and burden in the BBN mouse model of bladder cancer
Authors: Nakanishi Masako , Choudhary Shilpa , Hegde Poornima , Pilbeam Carol , Rosenberg Daniel , Taylor John A. 
Published: February 2011

Abstract
Introduction and Objective: Prostaglandins (PG) play a critical role in the development of solid tumors. Inhibition of cyclooxygenase-2 (COX-2), the committed step in PG synthesis, has been shown to impact tumor development in the BBN mouse model of bladder cancer. However, clinical translation has been impeded by the well documented cardiovascular problems with COX-2 inhibitors. Inhibition of other synthases downstream of COX-2 in the PG cascade may prove useful for chemoprevention or chemotherapy. In the following study, we evaluated the impact of gene deletion of membrane-associated prostaglandin synthase-1 (mPGES-1), the terminal synthase in the generation of PGE2, in the BBN mouse model.
Methods: Two month old male C57Bl/6 mice with global homozygous deletion for Ptges (mPGES-1 KO) and wild-type (WT) were treated with and without BBN in drinking water (n=5/grp) for 23 weeks. Bladders were harvested, weighed, fixed, step sectioned and evaluated by H&E for pathologic stage and grade and percent involvement of tissue by tumor. Urine was collected prior to sacrifice and evaluated for PGE-2 metabolites (PGEM) by ELISA.
Results: All animals had high-grade cancer at the time of euthanasia. WT bladders were significantly heavier than KO bladders (mean 0.18 vs 0.04 g respectively; p=0.03). Four of 5 WT mice had pT3 and one pT2 disease. Three of 5 KO mice had pT1 and 2 had pT2 disease. % tissue involvement was significantly less in the KO animals as well (54 vs 87%, p=0.03). Pearson's correlation for bladder weight and percent tumor involvement was 0.73 (p=0.02). Pathologic stage was dependant on genotype by Wilcoxon Rank Sum Test (p=0.02). Urine metabolites were reduced 50% in the KO compared to WT animals (mean 18.9 vs 45.2 pg/ml respectively; p&lt;0.01).
Conclusions: Genetic deletion of mPGES-1 resulted in significant decreases in PGE-2 as evidenced by lower urinary PGEM and in pathologic stage and % tissue involvement by tumor. Increased bladder weights in the WT mice compared to KO mice were directly related to the increased tumor burden. These results suggest that inhibitors of mPGES-1 may prove to be an alternative to COX inhibition and possibly prove useful in the management of high-grade bladder 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 2461.
Abstract 2468: Selective aldosterone blocker inhibits murine hepatocellular carcinoma development via angiogenesis suppression
Authors: Kaji Kosuke , Yoshiji Hitoshi , Ikenaka Yasuhide , Noguchi Ryuichi , Shirai Yusaku , Fukui Hiroshi 
Published: February 2011

Abstract
It is now widely recognized that angiogenesis is a crucial step in the development of tumors, including hepatocellular carcinoma (HCC). Therapies targeting the tumor vessels have proven successful for cancer treatment in experimental models and, in the clinical practice, several anti-angiogenic agents have already been employed. The renin-angiotensin-aldosterone system (RAAS) has also become known as a prerequisite for tumor angiogenesis, including HCC. We previously reported that angiotensin-II (AT-II) plays an important role in HCC development, and that suppression of AT-II by angiotensin-converting enzyme (ACE) inhibitor attenuated the tumor growth of HCC via suppression of intra-tumoral angiogenesis. Recent studies have also suggested the possible involvement of aldosterone (Ald) in neovascularization, although the actual role of Ald in tumor angiogenesis is still vague. The aim of our current study was to elucidate the effect of eplerenone (Epl), a clinically used selective Ald blocker, on HCC development, especially in conjunction with angiogenesis, using subcutaneous HCC model. To create an allograft model, we injected 1×106 of BNL-HCC cells into the flanks of BALB/c mice. The administration of Epl by daily gavage at a dose of 100 mg/kg/day was started on day 14, when the mean tumor volume was ∼ 200 mm3. The tumor volume was measured twice a week, and the mice were killed 35 days after tumor cell implantation. Administration of Epl at clinically comparable low dose could suppress HCC development as compared with the non-treated control. Epl treatment resulted in a marked increase of TUNEL-positive apoptosis in the tumor, whereas Ki67-positive tumor cell proliferation was not altered. Both CD31-immunopositive neo-vessels and VEGF expression in the tumor were markedly suppressed by this treatment in a magnitude similar to the inhibitory effect on the tumor growth. Our in-vitro study showed that Epl significantly suppressed the Ald-induced endothelial proliferation and tubular formation via inhibition of phosphorylation of the extracellular signal-regulated kinase 1/2. On the other hand, neither Ald nor Epl affected the proliferation of HCC cells. In conclusion, these results indicated that aldosterone plays a pivotal role in HCC development via VEGF-mediated tumor angiogenesis, and that Epl may be a potential new strategy for HCC therapy in the future.
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 2468.
Abstract 2469: Combination of branched-amino acids and ACE inhibitor attenuates the insulin resistance-based hepatocarcinogenesis via angiogenesis suppression
Authors: Shirai Yusaku , Yoshiji Hitoshi , Ikenaka Yasuhide , Noguchi Ryuichi , Kaji Kosuke , Fukui Hiroshi 
Published: February 2011

Abstract
A strong correlation between insulin resistance (IR) and hepatocellular carcinoma (HCC) has recently been identified, although little is known about the possible mechanisms involved. IR is a consistent finding in patients with type 2 diabetes mellitus (DM), and a close interaction between DM and HCC has been documented. Since neovascularization plays an important role in HCC including hepatocarcinogenesis, an angiostatic therapy would be a promising approach for chemoprevention against HCC. The aims of this study were to elucidate the role of angiogenesis in IR-based hepatocarcinogenesis, and to elucidate the therapeutic effect of combination of clinically used branched-chain amino acids (BCAA) and angiotensin-converting enzyme inhibitor (ACE-I), in conjunction with neovascularization. The combined effects on the development of liver enzyme-altered pre-neoplastic lesions, angiogenesis, and several indices were elucidated in obese diabetic rats. We also performed several sets of in-vitro experiments to examine the mechanisms involved. The IR status directly accelerated hepatocarcinogenesis, and treatment with both BCAA and ACE-I markedly inhibited the development of pre-neoplastic lesions under the condition of IR along with suppression of angiogenesis and VEGF expression in the liver. The combination treatment with BCAA and ACE-I exerted more potent inhibitory effects than single-agent treatments. Our in-vitro study demonstrated that BCAA and ACE-I inhibited the endothelial tubular formation almost in parallel with suppression of development of pre-neoplastic lesions. This combination regimen with BCAA and ACE-I showed a marked chemopreventive effect against hepatocarcinogenesis along with suppression of neovascularization and VEGF expression in obese diabetic rat as compared with either single-agent treatment. These inhibitory effects were achieved at clinically comparable low doses. Since both BCAA and ACE-I are widely used in the clinical practice, this combination therapy may represent a potential new strategy for chemoprevention against IR-based HCC in the future.
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 2469.
Abstract 248: Functional characterization of MED29 gene in pancreatic cancer
Authors: Kuuselo Riina , Savinainen Kimmo , Kallioniemi Anne 
Published: February 2011

Abstract
Pancreatic cancer is a highly aggressive malignancy characterized by rapid progression and an extremely poor prognosis. More knowledge is needed to better understand the mechanisms of the disease pathogenesis. Identification of new disease genes can improve our understanding about the biology of pancreatic cancer and might provide us tools for improving both diagnostics and treatment.
Previously, we performed a detailed characterization of the 19q13 locus, one the recurrently amplified regions in pancreatic cancer, and identified a set of putative amplification target genes that showed consistent overexpression in amplified cell lines versus non-amplified cell lines. Subsequent high-throughput RNAi screen targeting genes within the amplified region revealed a number of genes whose downregulation led to decreased cell viability in the amplified but not in the non-amplified cells. Of these, the mediator complex subunit 29 (MED29) was consistently overexpressed in all amplified cell lines and had the most dramatic effect on cell viability. By flow cytometry analysis, we showed that MED29 silencing resulted in G0/G1 cell cycle arrest and increased apoptosis in the amplified PANC-1 cells. MED29 is a subunit of a large multiprotein complex that is involved in transcriptional regulation and may function both as a transcriptional repressor and enhancer. To further define the function of MED29 we constructed a lentiviral vector for MED29 gene delivery. Mouse embryonic fibroblasts (NIH/3T3) and two pancreatic cancer cell lines with low basal MED29 expression (MIAPaCa2 and Hs700T) were transduced with a lentivirus vector containing MED29. Stable MED29 expression was confirmed in all three cell lines by quantitative RT-PCR and western blot analysis. MED29 expression led to statistically significant changes in proliferation and/or survival in both the NIH/3T3 cells and the pancreatic cancer cells. Finally, MED29 overexpressing human pancreatic cancer cell lines were subcutaneously inoculated into immunocompromized mice to follow tumor growth in vivo. Significant growth difference was observed between MED29 expressing cancer cells compared to control cells when injected into mice. To conclude, our results implicate MED29 as an important regulator of growth and survival in pancreatic cancer both in vivo and in vitro.
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 248.
Abstract 2487: Mechanism of action KX01 (KX2-391), a novel tubulin polymerization and Src signaling inhibitor proceeding to Phase II clinical trials
Authors: BU YAHAO , Smolinski Michael , Qu Jun , Kazim Latif , Gelman Irwin , Dyster Lyn , Hangauer David 
Published: February 2011

Abstract
KXO1 (KX2-391) has completed Phase I clinical trials in cancer patients and is now proceeding to Phase II. KXO1 was first characterized as a Src signaling inhibitor that exhibits potent anti-proliferative activity against a broad range of solid and liquid human cancers in vitro and in mouse models, including synergistic activity with other drugs. Using photo-affinity labeling technology, we have discovered that KXO1 also binds to tubulin at a novel binding site, and inhibits tubulin polymerization. KXO1 leads to cell cycle arrest at M phase with subsequent cell death mediated by canonical apoptosis pathways including phosphorylation of Bcl-2, loss of mitochondrial membrane permeability, and activation of caspases. Interestingly, inhibition of caspase activity by Z-VAD-FMK abrogates KXO1 induced cell death of HT29 and LNCaP cells but not in PC3-LN4 cells, suggesting the existence of caspase independent pathways capable of executing KXO1-induced cell death in certain cell types. In multi-drug resistant cancer cell lines, which overexpress p-glycoprotein, KXO1 still has equally potent anti-proliferative activity with GI50's in the low nanomolar range. KXO1 also exhibits strong anti-angiogenesis and vascular disrupting activities as revealed by an in vitro vasculature tube formation assay. KXO1 demonstrates robust activity in prostate cancer mouse xenograft models. The safety, tolerability and MTD were determined for KXO1 in a Phase 1 clinical study in patients with advanced malignancies refractory to conventional therapies. KXO1 was well tolerated at the MTD of 40 mg BID; only 1 out of 17 SAE's reported at or below the MTD was assessed as possibly KXO1-treatment related. Phase II clinical trial in prostate cancer patients will commence in early 2010.
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 2487.
Abstract 2502: p53 is critical for the Aurora B kinase inhibitor-mediated apoptosis in acute myelogenous leukemia cells
Authors: Ikezoe Takayuki , Yang Jing , Nishioka Chie , Yokoyama Akihito 
Published: February 2011

Abstract
We previously showed that AZD1152-HQPA, the inhibitor of Aurora B kinase potently induced growth arrest and apoptosis of various types of human leukemia cells including MV4-11 acute myelogenous leukemia (AML) cells, although the molecular mechanisms by which this class of kinase inhibitors induces apoptosis remain to be fully elucidated. We have recently established the MV4-11 subline, designated as MV4-11 TP53 R248W, which possesses transcriptionally inactive R248W mutation in the TP53 gene. MV4-11 TP53 R248W cells were relatively resistant to AZD1152-HQPA-mediated growth arrest, as measured by MTT and clonogenic assays. AZD1152-HQPA (10-100 nM, 48 hrs) strikingly induced apoptosis of MV4-11 cells, as assessed by Annexin V binding, loss of mitochondrial outer membrane potential, and activation of caspase cascade, in parallel with up-regulation of p53 and its target molecules Bax and Noxa. Notably, AZD1152-HQPA (10-100 nM, 48 hrs) induced polyploidy rather than apoptosis in MV4-11 TP53 R248W cells. The polyploid cells were eventually eliminated via apoptosis at later time period (72-120 hrs) in association with up-regulation of p73. Taken together, p53 plays an important role in AZD1152-HQPA induced growth arrest and early-onset of apoptosis in AML cells. P73 may mediate the late-onset of apoptosis to eliminate the polyploid cells caused by the inhibitor of Aurora B kinase.
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 2502.
Abstract 2521: The pan-RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF mutant-selective manner
Authors: Joseph Eric W. , Pratilas Christine A. , Poulikakos Poulikos I. , Tadi Madhavi , Wang WeiQing , Taylor Barry S. , Persaud Yogindra , Xing Feng , Halilovic Ensar , Viale Agnes , Chapman Paul , Tsai James , Bollag Gideon , Rosen Neal , Solit David B. 
Published: February 2011

Abstract
Activation of the RAS/RAF/MEK/ERK pathway occurs often in human cancer. Tumors with mutant BRAF and some with mutant RAS are dependent upon ERK signaling for proliferation and their growth is suppressed by selective inhibitors of MEK. In contrast, tumor cells with HER-kinase activation proliferate in a MEK-independent manner. These findings have led to the development of RAF and MEK inhibitors as anticancer agents. Like MEK inhibitors, the pan-RAF kinase inhibitor PLX4032 inhibits the proliferation of V600E BRAF mutant tumor cells, but not that of HER kinase dependent tumors. However, tumors with RAS mutation that are sensitive to MEK inhibition are insensitive to PLX4032. Whereas MEK inhibitors inhibit ERK phosphorylation in all normal and tumor cells, PLX4032 only inhibits ERK signaling in tumor cells with BRAF mutation. In contrast, the drug activates MEK and ERK phosphorylation in cells with wild-type BRAF. In mutant BRAF cells, the MEK and RAF inhibitors affect the expression of a common set of genes, whereas they have opposite effects on the expression of these genes in tumors with mutant RAS. Furthermore, PLX4032 inhibits ERK signaling output in mutant BRAF cells, but transiently activates it in tumor cells with wild-type RAF. Thus, PLX4032 inhibits ERK signaling output in a BRAF mutant-selective manner. These data suggest that PLX4032 may have a broader therapeutic index and help to explain the greater antitumor activity observed with this drug compared to MEK inhibitors, which inhibit ERK signaling in all 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 2521.