bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3460: Reactive oxygen species generated by cadmium play a role in the upregulation of aldo-keto reductase 1C3 in RPMI 2630 nasal carcinoma cells
Authors: Lee Yoon Jin , Hur Soo-Hark , Nam Hae Seon , Cho Moon Kyun , Lee Sang Han 
Published: February 2011

Abstract
Cadmium (Cd) is a carcinogenic metal which induces oxidative stress through the generation of reactive oxygen species (ROS). Therefore, the ability of cells to up-regulate their antioxidant enzymes is fundamental in the protection of cells and tissues from oxidative damage. In probing the possible survival mechanism of cancer cells to Cd-induced oxidative stress, we examined the ability of Cd to regulate the level of aldo-keto reductase 1C3 (AKR1C3), which has an anti-oxidative role that catalyzes the reductive detoxification of reactive aldehydes and ketones. Exposure of cells to Cd induced a dose- and time-dependent increase in the AKR1C3 expression in the RPMI 2640 nasal septum carcinoma cells, and this up-regulation was blocked by the free radical scavenger N-acetylcysteine (NAC). Additionally, we confirmed that Cd triggered a rapid increase in the intracellular ROS levels, and this increase was inhibited by pretreatment with NAC, which suggests that the up-regulation of AKR1C3 expression involves ROS signaling. Furthermore, pretreatment of cells with LY294002, a pharmacologic inhibitor of phosphatidylinositol-3-kinase (PI3K), suppressed the Cd-augmented AKR1C3 expression; however, inhibition of PKC or MEK1/2 signaling with Go6976 or PD98059, respectively, did not alter Cd-induced AKR1C3 expression. Collectively, these data suggest that Cd can modulate the expression of the AKR1C3 by activation of PI3K via the generation of ROS in RPMI2640 cells, which would contribute to adaptive response to oxidative stress.
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 3460.
Abstract 3466: Increased steady-state levels of microtubules in aberrant distributions in Ni+2 ion-/MCA-transformed C3H/10T1/2 mouse embryo cell lines
Authors: Pehl-De Silva Aruni T. , Samala Preethi , Lee Hongkyu , Landolph Joseph R. 
Published: February 2011

Abstract
We previously found amplification of the Ect-2 proto-oncogene, and higher steady-state levels of ect-2 mRNA and protein, in Ni+2 ion- and MCA-transformed C3H/10T1/2 (10T1/2) mouse embryo fibroblast cell lines. Here, we tested the hypotheses that there were 1) increased steady-state levels of microtubules in Ni+2/MCA-transformed 10T1/2 cell lines, 2) aberrant distributions of microtubules in transformed cell lines, and 3) increases in cross sectional areas of transformed cell lines. Log phase Ni+2 ion- and MCA-transformed and non-transformed 10T1/2 mouse embryo cells were stained separately with fluorescent antibodies to alpha tubulin or beta tubulin, then visualized using confocal microscopy (n=8). The number of microtubules/cell and cross sectional areas of stained cells were quantified using the volocity image analysis program, and ratios of (microtubules in transformed cell lines/microtubules in non-transformed 10T1/2 cells) were determined. In non-transformed 10T1/2 cells, microtubules were distributed homogeneously. In transformed cells, microtubules were often present as large aggregates in cells, and shapes of transformed cells were aberrant compared to shapes of non-transformed 10T1/2 cells. Compared to non-transformed 10T1/2 cells, MCA Cl 16, NiS3A1, NiS7A1 and NiO2C3 cell lines had a 2.1 (p &lt; 0.001), 1.5 (p &gt; 0.05), 1.8 (p &gt; 0.05) and 1.9 (p &lt; 0.05) fold higher fluorescent intensity for alpha tubulin, respectively. Compared to non-transformed 10T1/2 cells, MCA Cl 16, NiS3A1, NiS7A1 and NiO2C3 had 2.5 (p &lt; 0.05) 1.7 (p&lt;0.05), 1.8 (p&gt;0.05) and 1.1 (p&lt;0.05) fold-higher beta tubulin fluorescence intensity relative to 10T1/2 cells. Transformed cell lines showed 1.9 - 2.5 significant (p&lt;0.1) fold-increases in cross-sectional area compared to non-transformed 10T1/2 cells (n = 8). We concluded MCA-/Ni+2 ion-transformed 10T1/2 cells had higher steady-sate levels of microtubules, present in aberrant distributions, and transformed cells were larger than non-transformed cells. Supported by Grant ES03341 from U. S. N. I. H., funding from the M. S. Program in the Dept. of Molecular Microbiology/Immunology at USC, and discretionary funding, to JRL.
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 3466.
Abstract 3467: Repeated particulate chromate exposure induces chromosome instability and a DNA double strand break repair-deficient phenotype in human lung cells
Authors: Wise Sandra S. , Holmes Amie L. , Xie Hong , Pelsue Stephen , Thompson W. Douglas , Wise John P. 
Published: February 2011

Abstract
Particulate hexavalent chromium (Cr(VI)) is a potent respiratory carcinogen with widespread human exposure. The particulate form, for example lead chromate, has been determined to be the most toxic and carcinogenic form. These particles impact at bifurcation sites of the lung and persist in the respiratory tract. Chromosome instability (CIN) is a hallmark of lung cancer with cells exhibiting both translocations and severe aneuploidy. However, the ability of Cr(VI) to induce translocations is unknown. We exposed human lung cells to lead chromate for three sequential 24 h periods, each separated by about a month. After each treatment, cells were seeded at colony forming density, cloned, expanded and retreated. Each generation of clones were tested for their chromium sensitivity, chromosome complement and DNA repair capacity. We found that after the first treatment, lead chromate-treated cells exhibited a normal chromosome complement though a few clones showed an increase in relative survival. After the second exposure, more than half of the clones acquired an abnormal karyotype including numerical and structural alterations. The third treatment resulted in more abnormal clones as well as previously abnormal clones acquiring additional abnormalities. Clones were also treated with soluble Cr(VI) for 24 h followed by a 24 h recovery period to measure DNA double strand break repair. Abnormal clones showed little or no reduction in H2A. X foci formation after 24 h recovery suggesting that these clones had acquired a DNA double strand break repair- deficient phenotype. This work was supported by NIEHS grant ES016893 (J.P.W.).
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 3467.
Abstract 3471: Reciprocal roles of cytochromes P4501A1 and 1A2 in polycyclic aromatic hydrocarbon (PAH)-mediated tumorigenesis in mice: Implications for lung cancer in humans
Authors: Moorthy Bhagavatula , Wang Lihua , Jiang Weiwu 
Published: February 2011

Abstract
Humans are constantly exposed to environmental carcinogenic polycyclic aromatic hydrocarbons (PAHs) through cigarette smoke, diesel exhausts, charcoal-broiled meats, etc. Cytochrome P4501A (CYP1A) enzymes play important roles in the activation of PAHs such as 3-methylcholanthrene (MC) to carcinogenic DNA-binding metabolites. The resulting DNA adducts may lead to mutations of tumor suppressor genes such as p53, thereby leading to tumorigenesis. In this study, we tested the hypothesis that CYP1A1 and 1A2 have reciprocal roles in PAH-mediated tumorigenesis. Eight week-old female wild type (WT) (A/J) mice or mice lacking the gene for CYP1A1 or CYP1A2 on the A/J background were treated with a single dose of MC (40 µmol/kg), benzo[a]pyrene (BP), or vehicle (corn oil), and liver and lung tumors were studied after 28 weeks. While 100% of WT or Cyp1a2-null mice exposed to MC showed lung tumors after 28 weeks, about 80% of the Cyp1a1-null mice showed lung tumors. However, there were striking differences in the Cyp1a1-null and Cyp1a2-null in regard to lung tumor multiplicities and sizes of tumors. The WT mice treated with MC had about 15 lung tumors/animal. On the other hand, the Cyp1a2-null mice displayed about 40 lung tumors/animal, while the Cyp1a1-null mice showed about 2-3 tumors/mouse. Also, the tumor sizes were much larger in the Cyp1a2-null mice, compared to the much smaller sizes in the Cyp1a1-null mice. Although BP was less potent in inducing lung tumors in the WT mice compared to MC, it was similar to MC In that tumors were suppressed in the Cyp1a1-null mice and augmented in the Cyp1a2-null mice. Immunohistochemical studies showed that CYP1A1 was overexpressed in the tumorous portions of the lung in the Cyp1a2-null or WT mice, compared to non-tumorous regions, These results suggest that CYP1A1 contributes to the formation of tumorigenesis by PAHs, while CYP1A2 plays an important role in the protection against carcinogenesis mediated by PAHs, presumably through it role in PAH detoxification. In conclusion, our results strongly suggest that CYP1A1 and 1A2 could be novel candidates for cancer prevention and therapy though either inhibition of CYP1A1 or induction of CYP1A2. Thus, CYP1a1-null and Cyp1a2-null mice could be developed as novel animal models for future cancer prevention and/or therapeutic intervention in humans exposed to environmental PAHs. (Supported by NIH grant ES009132.)
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 3471.
Abstract 3473: Prolonged exposure to zinc chromate induces numerical chromosome instability via centrosome amplification in human lung cells
Authors: Holmes Amie L. , Wise Sandra S. , Pelsue Stephen , Lingle Wilma , Salisbury Jeffery , Gallagher Jamie , Wise John P. 
Published: February 2011

Abstract
Lung cancers are often characterized by numerical chromosome instability. Hexavalent chromium (Cr(VI)) is a well-known human lung carcinogen; however, its carcinogenic mechanism remains unknown. Studies show that solubility plays a key role in its carcinogenicity, with the particulate, or insoluble, compounds being the most potent carcinogens. Epidemiological and whole animal studies pinpoint particulate zinc chromate as the most potent Cr(VI) carcinogen; however, few studies have investigated its carcinogenic mechanism. Therefore, the goal of this study was to determine if zinc chromate induces numerical chromosome instability in human lung cells. We found that exposure to zinc chromate for 24 h did not induce aneuploidy but longer exposures induced both concentration- and time-dependent increases in aneuploid metaphases. For example, exposure to 0.1, 0.15 and 0.2 ug/cm2 zinc chromate for 120 h induced 28, 40 and 44 percent aneuploid metaphases, respectively, with increases in hypodiploid, hyperdiploid and tetraploid metaphases. Consistent with the aneuploidy data, a 24 h exposure to zinc chromate did not induce centrosome amplification but more chronic exposures induced concentration- and time-dependent increases in centrosome amplification in both interphase and mitotic cells. Exposure to 0.1, 0.15 and 0.2 ug/cm2 zinc chromate for 120 h induced centrosome amplification in 13.9, 18 and 21.3 percent of interphase cells and 21, 33 and 46 percent of mitotic cells. In order to determine the mechanism of centrosome amplification, we investigated the number of centrioles in each centrosome and found that cells with amplified centrosomes exhibited centrosomes with normal centriole pairs and centrosomes with centriolar defects indicating multiple mechanisms are involved in zinc chromate-induced centrosome amplification. Lastly, we found that chronic exposure to zinc chromate induced a prolonged G2 arrest. All together, these data indicate that chronic exposure to zinc chromate induces numerical chromosome instability via centrosome amplification in human lung cells. This work was supported by NIEHS grant ES016893 (J.P.W.), cooperative agreement #EP-08-01 through the Maine Space Grant Consortium (J.P.W.), EPA GRO Fellowship MA-91685401 (A.L.H.) and the Maine Center for Toxicology and Environmental Health at the University of Southern Maine.
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 3473.
Abstract 3476: Combined blockade of IGF-I receptor and VEGF for gastric cancer
Authors: Adachi Yasushi , Yamamoto Hiroyuki , Li Hua , Ohashhi Hirokazu , Ii Masanori , Arimura Yoshiaki , Endo Takao , Kato Yasuo , Carbone David P. , Imai Kohzoh , Shinomura Yasuhisa 
Published: February 2011

Abstract
Background Insulin-like growth factor-I receptor (IGF-IR) signaling is required for tumorigenicity and tumor progression of gastrointestinal (GI) cancers. We have shown successful therapy for GI cancers using adenoviruses expressing dominant negative IGF-IR (IGF-IR/dn). On the other hand, IGF-IR signaling affects on vascular endotherial growh factor (VEGF) expression in some tumors. Here, we sought to evaluate the roles of IGF-IR on tumor angiogenesis and lymphangiogenesis and to develop targeting therapy for gastric cancer. Methods The impact of IGF signals on VEGF-A/C expression in gastric cancer cell was assessed. The effects of IGF-IR/dn alone and with bevacizumab on angiogenesis / lymphangiogenesis in mouse xenogfarts were assessed. Results IGFs induced expressions of VEGFs and up-regulated in vitro vascular vessel formation. IGF-IR/dn reduced those expressions and vascular formation. IGF-IR/dn down-regulated tumor size on mice via inhibiting both angiogenesis and lymphangiogenesis. The combination of IGF-IR/dn and bevacizumab was highly effective against tumors on mice. This combination reduced the expression of VEGF and induced apoptosis in the murine tumors most of all. Conclusions IGF-IR is involved in angiogenesis and lymphangiogenesis in gastric cancer. Targeting IGF-IR alone and with blocking VEGF may have therapeutic utility of prevention for gastric cancer progression.
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 3476.
Abstract 3479: SMAC mimetic (JP1201) sensitizes non small cell lung cancers (NSCLCs) to multiple chemotherapy agents and erlotinib in an IAP dependent but TNFα independent manner
Authors: Greer Rachel M. , Peyton Michael , Girard Luc , Xie Yang , Gazdar Adi F. , Harran Patrick , Wang Lai , Brekken Rolf A. , Wang Xiaodong , Minna John D. 
Published: February 2011

Abstract
Tumor cells have acquired resistance to apoptotic stimuli, which is thought to contribute to chemotherapy resistance. Therefore strategies to re-engage apoptotic cascades have strong therapeutic potential. One family of proteins that is key in deregulating apoptosis are the Inhibitors of Apoptosis Proteins (IAPs), which function by binding to and inhibiting caspases, and are in turn inhibited by second mitochondrial activator of caspases (SMAC). One strategy to re-sensitize tumor cells to apoptosis is to create small molecule mimetics of SMAC, such as JP1201 (Joyant Pharmaceuticals). Initial tests of JP1201 in lung cancer identified ∼15% of NSCLCs that were sensitive to low concentrations of JP1201 as a single agent. In all cases sensitive NSCLCs expressed TNFα which was required for single agent drug sensitivity (Peterson et al., 2007). To extend these findings to the large majority of NSCLCs and prepare for clinical trials, we tested 15 NSCLC lines that are resistant to single agent JP1201 (IC50 ≥ 100 µM) in combination with cisplatin, doxorubicin, gemcitabine, erlotinib, paclitaxel, and vinorelbine in a 5 day MTS based microtiter assay. We find great heterogeneity among NSCLCs in tumor cell response phenotypes to combined JP1201 + chemotherapy agents and that for each NSCLC at least one chemotherapy was sensitized by JP1201 100 to 10,000 fold (significant combination indices). Of note we found no NSCLC where cisplatin was sensitized by JP1201. Surprisingly, we also found examples of antagonism when JP1201 is added. Using siRNAs targeted to cIAP1, cIAP2, and XIAP we found that for gemcitabine, XIAP is the key IAP whose inhibition by JP1201 leads to sensitization, while for paclitaxel and vinorelbine, knockdown of any of the three IAPs sensitizes NSCLCs. None of the treatments induce secretion of TNFα or TRAIL (detected by ELISA) in this panel of NSCLCs. NOD/SCID mice bearing NSCLC NCI-H1395 xenografts were randomized (8 mice per group) to 3 weeks of treatment with saline, 25 mg/kg gemcitabine, 2.4 mg/kg vinorelbine, 6 mg/kg JP1201, gemcitabine + JP1201, and vinorelbine + JP1201. Tumor burden was reduced 60% in mice treated with gemcitabine + JP1201 compared to gemcitabine alone, and 70% in mice treated with vinorelbine + JP1201 compared to vinorelbine alone. We conclude that preclinical studies show the combination of JP1201 with chemotherapy is a valid therapeutic strategy for NSCLC.
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 3479.
Abstract 3481: Establishment of preclinical models to identify clinically useful combinations of trifunctional antibodies with chemotherapy
Authors: Dettmar Kirsten , Atz Judith , Lindemann Carsten , Schroeder Petra , Eberhardt Andrea , Kluge Michael 
Published: February 2011

Abstract
The trifunctional bispecific antibodies catumaxomab (anti-EpCAM x anti-CD3) and ertumaxomab (anti-HER-2/neu x anti-CD3) exert their mechanism of action by simultaneous recruitment and activation of two different types of immune effector cells at the tumor site. The interaction of different immune effector cells results in efficient elimination of tumor cells by several killing mechanisms including T-cell cytotoxic responses and direct effects mediated by accessory cells.
Effective treatment of cancer is essentially based on cytotoxic drugs that kill tumor cells or inhibit their proliferation. However, the commonly observed hematotoxicity of chemotherapeutics is regularly associated with some degree of immunosuppression. On the other hand, some of these chemotherapeutic agents are reported to support or even enhance the anti-tumoral effect of immunotherapeutic drugs in certain doses.
A largely intact immune system is the key for trifunctional antibodies to exhibit their full mode of action. Since chemotherapy might impact the number and function of immune effector cells, we evaluated in different preclinical in vitro models whether the efficacy of trifunctional bispecific antibodies would be influenced when combined with chemotherapeutic drugs (5-FU and cisplatin).
The preclinical studies performed included in vitro cytotoxicity assays with established tumor cell lines evaluating potential synergy by using the method of Chou and Talalay. Furthermore, results from 3D tumor spheroids and from an autologous human ex vivo setting are presented.
In addition, immune cells from cancer patients were obtained at different time points during and after chemotherapy and were assessed for their in vitro cytotoxicity mediated by trifunctional antibodies.
So far the results from the different in vitro assay systems used indicate synergy for the combination of the trifunctional antibodies with 5-FU and cisplatin. Furthermore, no negative influence of these chemotherapeutic drugs was observed on the trifunctional mode of action in vitro. These results provide a basis for the possible combination of these drugs with trifunctional antibodies in the clinical setting.
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 3481.
Abstract 3487: Synergy with combined inhibition of upstream EGFR-HER2 and downstream RAF-MEK nodes in breast cancer cells with activating RAS and RAF mutations
Authors: Nagaria Teddy S. , Greer Peter A. , Sangrar Waheed 
Published: February 2011

Abstract
Targeted therapies have been developed to target a variety of oncogenic proteins implicated in breast cancer. These include epidermal growth factor receptor (EGFR), epidermal growth factor receptor type-2 (HER-2), as well as RAS, RAF and MEK, which together comprise the mitogen activated protein kinase (MAPK) cascade. Herein, we explored the therapeutic efficacy of tyrosine kinase inhibitors of EGFR and HER-2 by testing these inhibitors on a human metastatic breast cancer cell line MDA-MB-231. We also determined whether inhibiting tyrosine kinase receptors correlated with the activity of downstream nodes such as MEK and ERK. We report that EGFR inhibitors potently inhibited the phosphorylation of EGFR, but had no effect on MEK and ERK activity, which were observed to be constitutively active in this cell line. Interestingly, MEK/ERK insensitivity correlated with cytotoxic resistance of MDA-MB-231 cells to EGFR inhibitor treatment. In contrast, targeting both EGFR and HER-2 with a dual EGFR/HER-2 inhibitor Lapatinib resulted in significantly improved cytotoxic effects and a partial reduction in MEK and ERK activity. In comparison to the effects of Lapatinib, targeting RAF with Sorafenib resulted in almost complete abrogation of MEK/ERK signaling activity and enhanced cytotoxicity. Our results are consistent with earlier reports suggesting that MAPK signaling is required for MDA-MB-231 cell survival, consistent with the reported presence of activating RAS and RAF mutations in this cell line. Our data highlight the role of RAS and RAF mutations in the uncoupling of downstream nodes (MEK and ERK) from upstream receptor activation. Lastly, the MEK inhibitor U1026 fully inhibited ERK activity but exhibited poor cytotoxicity. This suggests that MDA-MB-231 cells may circumvent MEK inhibition through upstream survival pathways mediated by activated RAS or RAF. An apparent synergistic cytotoxic effect was noted when combining Sorafenib and U1026. Cytotoxic synergy was also observed when Sorafenib was combined with Lapatinib. These putative synergistic drug combinations show promise in that they could deliver significant cytotoxic effects with reduced doses. We find there is merit in targeting multiple oncogenic nodes concurrently to promote additional therapeutic benefits. This also shows potential use in targeting a broader variety of cancer cells that harbor constitutive MAPK signaling associated with oncogenic RAS or RAF mutations.
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 3487.