bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 941: Elucidation of chemopreventive effects of aerosolized rapamycin and dietary myoinositol by mechanistic biomarkers in mouse lung
Authors: Sharma Sheela , Lee Jin , Wong Brian , Sochaski Mark , Dennis Phillip A. , Steele Vernon E. 
Published: February 2011

Abstract
Rapamycin, an approved anti-rejection drug for patients undergoing organ transplantation, has shown antitumor activity in preclinical studies and clinical trials. However, concerns regarding the prevalence of pneumanitis in a small percentage of patients receiving the drug by injection have prompted us to test an alternative route of administration. Myoinositol is another agent that has shown excellent chemopreventive activity both in preclinical and clinical settings and is very well tolerated in humans. The objective of the current study is to investigate whether aerosolized rapamycin or myoinositol fortified diet can inhibit two key biomarkers of lung cancer, activated Akt and mTOR, in lungs and test the feasibility of two dosing regimens (continuous or intermittent dosing) on the same biomarker expression at multiple time points after the last dosing. Female A/J mice (8 wks old) were exposed to 5 different doses of myoinositol (0.01, 0.03, 0.1, 0.3 and 1% diet) or rapamycin by inhalation (0.001, 0.01, 0.1, 1 and 10 mg/kg) continuously for 5 days or every other day for 3 days in two separate experiments. After the last exposure, blood concentration (measured by GC-MS) and effect of each agent on phosphorylated-AKT (phospho-AKT at Thr308) and mTOR (phospho-S6 at Ser235/236) was assessed by immunohistochemistry. There was a good correlation between the dose-dependent increase in blood concentration of myoinositol (20 − 255 μM) or rapamycin (0.033-1.75 μM) and corresponding dose-dependent decrease in the expression of phospho-AKT (21-85%) and mTOR (10-69%) or phospho-AKT (54-60%) and mTOR (28-73%), respectively, in the lung compared to untreated controls. Interestingly, there was no significant difference between the two regimens in reducing the biomarker expression by either myoinositol or rapamycin and the expression levels continued to remain the same for up to 3 days after the last exposure or treatment. No toxicity was observed during or after the exposure and all animals showed normal body weight gain. In conclusion, this study showed that both rapamycin and myoinositol showed significant inhibition of phospho-AKT and phospho-mTOR expression from the basal level (AIN-76A diet control for myoinositol or air control for rapamycin) and that both these agents can be administered intermittently instead of continuously to observe similar effects. In addition, subsequent cancer prevention studies that are planned by administering agents at selected intervals should reduce or eliminate any associated toxicities from long term exposures (Supported by NCI #N01-CN-53301).
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 941.
Abstract 942: Effects of maternal and postnatal folic acid supplementation on genomic DNA methylation in the mammary glands in a chemical rat model of mammary tumorigenesis
Authors: Ly Anna , Lee Hanna , Chen Jianmin , Sohn Kyoung-Jin , Sie Karen K. , Croxford Ruth , Renlund Richard , Thompson Lilian , Kim Young-In 
Published: February 2011

Abstract
Background: Widespread loss of genomic DNA methylation is an early and consistent epigenetic event in cancer development including breast carcinogenesis. Folate, an essential co-factor in the transfer of one-carbon units, has been shown to modulate both cancer risk and genomic DNA methylation. We recently observed that folic acid (FA) supplementation provided in utero and in early postnatal life significantly increased risk of mammary tumors in the offspring in the dimethylbenzanthracene (DMBA) rat model. To determine a potential underlying mechanism of FA-mediated mammary tumor development, we investigated the association between global DNA methylation, DNA methyltransferase (DNMT) activity, FA supplementation, and mammary tumor status in the offspring.
Methods: Female Sprague-Dawley rats were placed on a control diet (2 mg FA/kg diet) or a supplemented (5 mg) diet for 3 weeks prior to breeding and throughout pregnancy and lactation. At weaning, female pups were randomized to the control or supplemented diet. At 7 weeks of age, all pups received a single intragastric dose (5 mg) of DMBA to induce mammary tumors. At 28 weeks of age, plasma, mammary gland and liver folate and plasma homocysteine concentrations were determined and mammary tumors were enumerated and histologically confirmed. Genomic DNA methylation and DNMT activity were determined in non-neoplastic mammary glands.
Results: Plasma, liver, and mammary folate and homocysteine concentrations accurately reflected dietary FA levels at weaning and 28 weeks of age (p&lt;0.05). A significant interaction was observed between genomic DNA methylation and mammary adenocarcinoma status in the offspring (p&lt;0.001), indicating that among tumor-free offspring, genomic DNA methylation was significantly decreased by maternal FA supplementation. In addition, in offspring bearing at least one adenocarcinoma, genomic DNA methylation was significantly decreased regardless of dietary FA intervention. Postweaning FA supplementation independently decreased DNMT activity in the offspring (p=0.05).
Conclusions: Our data suggest that decreased genomic DNA methylation and DNMT activity associated with maternal and postweaning FA supplementation might be a mechanism by which maternal and postweaning FA supplementation increased mammary tumorigenesis in the offspring. Given the drastic increase in FA intake among women of childbearing age in North America, future studies are need to determine whether or not FA supplementation increases the risk of breast cancer through epigenetic mechanisms.
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 942.
Abstract 953: Benzyl isothiocyanate suppresses pancreatic cancer angiogenesis and invasion by inhibiting Akt and MMP-2
Authors: Boreddy Srinivas Reddy , Pramanik Kartick C. , Kandala Prabodh K. , Srivastava Sanjay K. 
Published: February 2011

Abstract
We have shown in our previous studies that benzyl isothiocyante (BITC) suppress the growth of pancreatic cancer cells by inhibiting the activation of NF-kB and STAT-3 without affecting the viability of normal HPDE cells. Further, we demonstrated that oral administration of BITC significantly blocked the growth of pancreatic tumor xenografts in vivo. In the present study, we examined the effect of BITC on pancreatic cancer angiogenisis and invasion. Our results demonstrate that 5-10µM BITC almost completely blocked neovasculture formation in an ex vivo chick chorio-allantoic membrane (CAM) model. In agreement with these results, in vivo matrigel plug assay in athymic nude mice also reveal that the hemoglobin content in the implanted matrigel plug was reduced by 70% in the mice which were orally fed 12µmol BITC for 7 days as compared to controls, suggesting reduced blood vessel formation. In a matrigel tube formation assay using mouse brain endothelial cells, BITC treatment significantly inhibited VEGF-induced tube formation. As compared to controls, 5µM BITC treatment for 36h caused a drastic reduction in the number of cells that migrated into the wounding area in a wound healing assay. Our results also showed that the tumor cell invasion was effectively (p&lt;0.001) inhibited by 50% in the BxPC-3 cells treated with 10 µM BITC for 24h in a transwell cell invasion assay. Since PI3K, Akt and MMP-2 are critically involved in tumor cell invasion, angiogenesis and metastasis we next evaluated the effect of BITC on these key signaling molecules. As expected, BITC treatment significantly reduced the expression as well as phosphorylation of PI3K at Tyr-458 and Akt at Ser-473 in BxPC-3 cells in a dose-dependent manner. In addition, the expression and mRNA level of MMP-2 was significantly down-regulated by BITC treatment in BxPC-3 cells. Furthermore, tissue inhibitor of metalloproteinases-2 (TIMP-2) level was also reduced by BITC. Taken together, our data strongly suggests the anti-angiogenic and anti-metastatic role of BITC in pancreatic cancer cells and warrants further clinical investigation. [Supported in part by RO1 grants CA 106953 and CA129038 (to SKS) awarded by National Cancer Institute].
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 953.
Abstract 956: Targeting prostate cancer chemoprevention via the androgen receptor in a preclinical mouse model
Authors: Koike Hiroyuki , De Velasco Marco A. , Miyazaki Yuka , Asahi Chiori , Ushida Hiroshi , Shimada Keiji , Yoshikawa Kazuhiro , Nishio Kazuto , Konishi Noboru , Uemura Hirotsugu 
Published: February 2011

Abstract
Prostate cancer is strongly associated with increasing age, with about 96 % of the cases occurring in men over 60 years of age. The high incidence and late age of onset make prostate cancer an ideal target for chemoprevention strategies as even a modest delay in carcinogenesis would significantly reduce the incidence of the disease. Chlormadinone acetate (CA) is one of the steroidal anti-androgen agents used in combined androgen blockade therapy as well as monotherapy for prostate cancer in Japan. However, no reports have been published for the chemopreventive potential of CA. We evaluated the efficacy of low-dose administration of CA to prevent or suppress prostate cancer using our PTEN conditional gene targeting mouse model.
Six-week-old mice were injected subcutaneously with CA (50 mg/kg 3X/week) until the age of 15 or 20 weeks. The genitourinary tracts (GUTs), consisting of the prostate, urethra, bladder, seminal vesicles and coagulating gland, were collected, weighed, fixed in formalin and imaged. GUT weights were significantly lower in CA-treated mice compared to untreated controls in a time dependent manner (P&lt;0.01). Morphometric image analysis performed on the GUT to measure the prostate area revealed significant shrinkage of the prostate gland in CA-treated mice vs. the corresponding controls (P&lt;0.001). Histopathological distribution analysis of normal, prostatic intraepithelial neoplasia (PIN) and tumor glands showed a decrease in the PIN but not normal or cancer glands in 15-week-old CA-treated mice compared to controls. However, similar analysis showed a dramatic decrease of cancer gland shrinkage in 20-week-old CA-treated mice with only marginal decreases of PIN compared to untreated controls. Immunohistochemical analysis of androgen receptor (AR) expression showed a significant decrease in nuclear localization and intensity CA-treated mice (P&lt;0.001). Proliferation analysis of tumors by PCNA immunostaining showed a 30% reduction in 20-week-old mice treated with CA compared to untreated control mice (P&lt;0.001). The apoptotic index in tumors if mice treated with CA increased three-fold to 3.16% compared to 1.12% on the corresponding control mice (P&lt;0.004). Our data suggests that chemopreventive treatment with CA does not prevent the incidence of prostate cancer, however, it does inhibit the growth and progression of prostate cancer. Our findings may reveal a promising prophylactic strategy for the chemopreventive treatment of prostate cancer in high-risk individuals.
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 956.
Abstract 957: Dietary flavonols protect against colorectal carcinogenesis in an AOM-DSS mouse model for colorectal cancer
Authors: Bobe Gerd , Young Matthew R. , Kim Young , Colburn Nancy H. 
Published: February 2011

Abstract
Background: Epidemiological studies suggest that a flavonol-rich diet inhibits colorectal carcinogenesis. Flavonols are a subgroup of polyphenols, which are found in fruits and vegetables usually glycosylated and are in particularly high concentrations in dry beans, onions, apples, and tea. The most consumed individual flavonols are in this order quercetin and one of its glycosylated forms rutin, kaempferol, myricetin, and isorhamnetin. Aim: To determine which individual flavonol is most protective against colorectal carcinogenesis in an inflammation-associated mouse colorectal carcinogenesis model (azoxymethane[AOM]/dextran sodium sulfate[DSS]-induced FVB mice). Methods: At 6 weeks of age, mice were injected intraperitoneally with AOM (10 mg/kg body weight). Mice then received for 1 week 2% DSS in the drinking water (1 or 1 and 4 weeks after AOM injection). Three days after the last DSS cycle, mice either remained on the AIN-93G diet or were switched to one enriched with 500 mg of kaempferol or equimolar concentrations of isorhamnetin, myricetin, quercetin, or rutin/kg of diet. Mice (n=32/group) remained for 85 days on the diets unless they had to be sacrificed earlier because of morbidity. A subset of mice was imaged using magnetic resonance imaging (MRI) at various times throughout the study. Results: Among the diets, mice on the control diet had the highest morbidity (50%) and mice on the isorhamnetin diet had the lowest morbidity (22%). Similarly, lesion number and size were lowest in mice on the isorhamnetin (16/mouse and 8.8 mm3/lesion) and the kaempferol (15/mouse and 7.4 mm3/lesion) diet compared to the control diet (21/mouse and 11.6 mm3/lesion). Image parameters detected different stages of colorectal carcinogenesis that can be modified by diet. Conclusion: All individual flavonols showed some protection against colorectal carcinogenesis with isorhamnetin and kaempferol being most efficacious. Studies are underway to identify serum, tissue, and imaging biomarkers of efficacy at earlier stages of colorectal carcinogenesis.
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 957.
Abstract 958: Recruitment of tumor-associated macrophages by cooperation of PGE2 pathway and infectious stimulation
Authors: Oshima Hiroko , Oguma Keisuke , Oshima Masanobu 
Published: February 2011

Abstract
Gastric cancer development is tightly associated with Helicobacter infection, which induces expression of COX-2 and mPGES-1 resulting in activation of PGE2 pathway in gastric mucosa. It has been established that PGE2 pathway plays a key role in chronic inflammation and tumorigenesis in the stomach. However, mechanisms of PGE2 or PGE2-induced inflammation underlying tumorigenesis have not been fully understood yet. On the other hand, tumor associated macrophages play an important role in tumorigenesis through expression of growth factors, induction of angiogenesis, remodeling and suppression of acquired immunity. We previously showed that macrophage infiltration was enhanced in K19-C2mE transgenic mouse stomach, in which PGE2 pathway is induced by expression of COX-2 and mPGES-1. Moreover, accumulated macrophages in gastric mucosa were activated, which was suppressed by treatment of the mice with antibiotics. These results suggested that both PGE2 pathway and infectious stimulation are important for macrophage infiltration and activation during tumorigenesis. To investigate the effect of PGE2 and infectious stimuli in gastric tumorigenesis, we generated germfree colony of K19-Wnt1/C2mE transgenic mice and examined gastric phenotypes. K19-Wnt1/C2mE mice develop dysplastic gastric tumors caused by simultaneous activation of Wnt signaling and PGE2 pathway. Importantly, germfree K19-Wnt1/C2mE mice showed significant suppression of gastric tumor development with decreased macrophage infiltration. Moreover, Helicobacter infection to germfree K19-Wnt1/C2mE mice induced gastric tumor development. These results indicate that infectious stimuli to gastric mucosa are required for tumor formation. We also found that PGE2 pathway together with bacterial infection induced expression of monocyte-attractant chemokine CCL2 in the gastric mucosa and macrophage cell line. Notably, infiltrated macrophages showed “alternatively” activated M2 properties, which are characteristics of tumor-associated macrophages. Finally, inhibition of COX-2/PGE2 pathway in K19-Wnt1/C2mE mice caused significant suppression of macrophage infiltration and gastric tumorigenesis. These results suggest that PGE2 signaling and bacterial infectious stimulation cooperatively recruit protumorigenic macrophages through induction of chemokines, and that recruitment of tumor-associated macrophages is one of the important mechanisms of PGE2 signaling in tumorigenesis.
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 958.
Abstract 962: Similar preventive effects of naproxen and NO-naproxen in a chemically-induced model of urinary bladder cancer: Dose dependency, gene expression and toxicity
Authors: Grubbs Clinton J. , Wang Yian , You Ming , Steele Vernon , Boring Daniel , Lubet Ronald 
Published: February 2011

Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) have been highly effective in preventing colon, urinary bladder, and skin cancers preclinically; and also in clinical trials of colon adenoma formation. However, certain NSAIDs cause gastrointestinal (GI) ulceration and may increase cardiovascular (CV) events. Naproxen appears to cause the lowest CV events of the common NSAIDs other than aspirin. NO-naproxen was tested based on the finding that adding a nitric oxide (NO) group to NSAIDs may help alleviate GI toxicity, as well as the expectation that the production of NO itself might be therapeutically effective. We examined these agents in the hydroxybutyl(butyl)nitrosamine (OH-BBN) rat urinary bladder cancer model beginning 2 weeks after the last dose of carcinogen. Naproxen at doses of 400, 200, 128 or 75 ppm in the diet greatly decreased the development of large urinary bladder cancers. NO-naproxen at 183 or 550 ppm caused striking decreases in the incidence of large tumors implying that both agents are similarly effective. The lower doses of these agents are well below the human equivalent dose based on standard scaling factors. We are presently treating rats with naproxen by gavage and collecting serum to directly compare the pharmacokinetics of naproxen in the rat and human. To determine whether there was any indication of NO release in NO-naproxen treated rats, microarrays were performed with liver and bladder tissues from treated rats. Minimal differences in gene expression changes between the two agents were observed. Also, an ARE related response in the liver, which one would have expected from NO, was not seen. Thus, the data are compatible with limited direct effects of NO on urinary bladder cancer prevention. Supported by the NCI contract number HHSN261200433001C.
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 962.
Abstract 965: Mechanistic studies of a dietary combination in cancer prevention: The effects of manganese superoxide dismutase on tumor suppressor gene activation
Authors: Robbins Delira F. , Morris Kerri , Zhao Yunfeng 
Published: February 2011

Abstract
Mechanistic Studies of a Dietary Combination in Cancer Prevention: The Effects of MnSOD on Tumor Suppressor Gene Activation
Reactive oxygen species can act as signaling transduction molecules modulating various pathways, such as the PI3K/Akt pathway. It is known that this pathway is constitutively activated in tumorigenesis contributing to protein synthesis, cell cycle progression, migration and survival. However, the PI3K/Akt pathway is negatively regulated by the major tumor suppressor protein PTEN. PTEN has dual specificity phosphatase activity regulating Akt phosphorylation as a lipid phosphatase; as well as, regulating cyclin D1 expression as a protein phosphotase. However, these are the roles of cytoplasmic PTEN. Recently, the nuclear roles of PTEN have received significant attention. Nuclear PTEN plays a major role in maintaining cellular homeostasis and stability by contributing to chromosome stability, DNA repair and cell cycle arrest. Previous studies have shown that PTEN nuclear localization is mediated by oxidative stress and may play a role in p53 stabilization. Nevertheless, MnSOD is considered to be a novel tumor suppressor gene. MnSOD has been defined as a nuclear encoded primary antioxidant enzyme localized in the mitochondria. We have shown in previous studies that the dietary combination Protandim reduced tumor incidence and multiplicity via the synergistic induction of superoxide dismutase enzymes. It has been shown that overexpression of MnSOD in in vivo models can suppress tumor formation via modulation of AP-1 binding. Therefore, it is imperative to look at how MnSOD may affect the process of apoptosis and the activation of tumor suppressor genes involved (i.e. PTEN and p53). Using our in vivo models (wildtype, MnSOD knockout, non-transgenic and MnSOD transgenic mice), we investigated how modulation of MnSOD expression may affect PTEN-mediated p53 stabilization, and how this contributes to chemoprevention. In addition, we explored how mutations in p53 may affect the PTEN-p53 interaction and its effects on tumor promotion via a gene transfection approach.
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 965.