bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2568: Acquired apoptosis resistance mediated by activation of the Akt/COX-2/Mcl-1 pathway in lung cancer cells
Authors: Chen Wenjie , Bai Lang , Wang Xia , Xu Shanling , Belinsky Steven A. , Lin Yong 
Published: February 2011

Abstract
Acquired apoptosis resistance plays an important role in acquired chemoresistance in cancer cells during chemotherapy. Based on our previous observations that acquired TNF-related apoptosis-inducing ligand (TRAIL)-resistance in lung cancer cells was associated with Akt-mediated stabilization of c-FLIP and Mcl-1, we further examined if the TRAIL-resistant cells also have acquired resistance to apoptosis induced by chemotherapeutics, such as cisplatin (CDDP) and adriamycin (Adr), and the mechanism underlying this resistance. By systematically delineating the signaling pathway for acquired apoptosis resistance using in vitro cell culture and in vivo xenografted tumor models, we determined that these TRAIL-resistant cells also have acquired resistance to apoptosis induced by chemotherapeutics such as cisplatin (CDDP) and adriamycin (Adr). We further found that COX-2 is dramatically overexpressed in cells with acquired apoptosis resistance. COX-2 appears to be a crucial mediator in acquired apoptosis resistance because suppressing COX-2 activity with chemical inhibitors or reducing COX-2 protein expression level with COX-2 siRNA dramatically alleviated resistance to therapeutic-induced apoptosis both in vitro and in vivo. Inhibiting Akt markedly reduced COX-2 expression, suggesting COX-2 is a downstream effector mediating apoptosis resistance of this cell survival kinase. Furthermore, the expression of Mcl-1 but not c-FLIP was significantly reduced when COX-2 was suppressed and knockdown of Mcl-1 substantially sensitized the cells to CDDP- or Adr-induced apoptosis. Our results establish a novel pathway that consists of Akt, COX-2, and Mcl-1 for acquired apoptosis resistance, which could be a molecular target for circumventing acquired chemoresistance in lung 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 2568.
Abstract 2571: The predictive biomarker for the resistance to antifolate
Authors: Uemura Takehiro , Oguri Tetsuya , Ozasa Hiroaki , Takakuwa Osamu , Tomita Yuki , Nakao Makoto , Suzuki Takeshi , Iwashima Yasuhito , Miyazaki Mikinori , Maeno Ken , Sato Shigeki , Ueda Ryuzo 
Published: February 2011

Abstract
Currently, several folate-based antimetabolites are used for cancer treatment. Pemetrexed (MTA) is new generation antifolate which inhibits multiple folate-requiring enzymes, mainly thymidylate synthase (TS). We cultured small lung cell cancer cell line, PC-6 in the presence of MTA and established two MTA resistant cell lines, PC-6/MTA-1.6 and PC-6/MTA-4.0, which grew vigorously in medium containing 1.6uM and 4.0uM, respectively. These cell lines showed cross resistance to methotrexate (MTX), but not to other cytotoxic agents including etoposide, vinorelbine and cisplatin. Among many ATP-binding cassette (ABC) transporters, only ABCC11/MRP8 (ABCC11) gene expression was markedly increased in PC-6/MTA-1.6 cells. In contrast, TS gene expression was markedly increased in PC-6/MTA-4.0 cells. ABCC11 gene expression was not increased in PC-6/MTA-4.0 cells. There were no changes in reduced folate carrier and folylpoly-gamma-glutamate synthetase expression level in MTA resistant cells. To determine if the higher expression of the ABCC11 in the PC-6/MTA-1.6 cells resulted in a greater efflux of drugs, we assayed the intracellular accumulation of MTX, which is known to be a substrate for ABCC11 in the PC-6 and PC-6/MTA-1.6 cells and found that MTX accumulation in PC-6/MTA-1.6 cells was lower than PC-6 cells. We found that decrease of ABCC11 expression by ABCC11 siRNA enhanced MTA and MTX cytotoxicity in PC-6/MTA-1.6 cells. Decreasing the expression of TS by small interfering RNA (siRNA) also enhanced MTA and MTX cytotoxicity in PC-6/MTA-4.0 cells. These results give a concept that resistance for antifolate is advanced as TS gene expression is increased, while ABCC11 may work in early phase of resistance when TS expression is not enough induced. TS and ABCC11 may be useful as predictive biomarkers for the resistance to antifolate.
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 2571.
Abstract 2574: Development and characterization of a potent immunotoxin targeting the Fn14 receptor on solid tumor cells
Authors: Zhou Hong , Marks John W. , Winkles Jeffrey A. , Yagita Hideo , Rosenblum Michael G. 
Published: February 2011

Abstract
TNF-like weak inducer of apoptosis (TWEAK) and FGF-inducible 14 (Fn14) are a TNF superfamily ligand-receptor pair involved in inflammation, oncogenesis, tumor invasion, migration, survival and resistance to chemotherapy. The Fn14 receptor is expressed at relatively low levels in normal tissues, but is known to be dramatically elevated in a number of tumor types, including brain and breast tumors. Thus, the TWEAK/Fn14 axis appears to be an excellent candidate for therapeutic intervention. We have developed an immunoconjugate designated ITEM4-rGel containing a high-affinity anti-Fn14 monoclonal antibody conjugated to recombinant gelonin (rGel), a highly cytotoxic, ribosome-inactivating n-glycosidase. The ITEM4-rGel conjugate was generated and purified and contained no contaminating free antibody or rGel. The final material contained both antibody + 1 rGel (major) and antibody + 2 rGel (minor) species. We analyzed Fn14 expression in human tumor cell lines using flow cytometry and Western blot analysis. Fn14 was expressed in a variety of tumor lines including breast, brain, bladder, skin, lung, ovarian, pancreatic, colon, prostate, and cervical tumor cell lines. Both ITEM4 and ITEM4-rGel were found to bind to cells to an equivalent extent. Confocal immunofluoresence studies showed that ITEM4-rGel specifically and rapidly (within 2 hrs) internalized into MDA-MB-231 breast cancer cells and T-24 bladder cancer cells but not into Fn14-deficient mouse embryonic fibroblasts. Cytotoxicity studies against 22 different tumor cell lines showed that ITEM4-rGel was highly cytotoxic to Fn14-expressing cells (IC50 ranged from 0.8 pM-25 nM) and was 50 to 0.5 ×106 fold more potent than free rGel. Minimum contact time studies showed that as little as 12 hr exposure achieved maximal cytotoxic effect. Mechanistic studies showed that ITEM4-rGel induced HMGB1 release following treatment of MDA-MB-231, T-24, AAB 527, and BxPC-3 cells. In addition, target cells showed induction of apoptosis, as measured by Annexin V staining and caspase-3 cleavage. ITEM4-rGel treatment also induced the non-canonical NF-κB pathway, up-regulated the tumor suppressor protein p53 and down-regulated survivin expression. Preliminary mouse xenograft tumor model studies are ongoing. These data suggest that the ITEM4-rGel construct may warrant further development as a novel therapeutic agent against a broad range of solid tumor types. Research conducted, in part, by the Clayton Foundation for Research (MGR), and supported by NIH grant NS55126 (JAW) and DOD Breast Cancer Concept Award BC086135 (JAW).
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 2574.
Abstract 2578: Efficacy of anti-CD22 antibody drug-conjugates in Ramos and Raji tumor xenograft models
Authors: Pan Chin , Chong Colin , Cortez Orville , Witte Alison , Nazeer Ayesha , Rao-Naik Chetana , Huber Mary , Stevens Alice , Zhang Qian , Masood Asna , Gangwar Sanjeev , King David , Devaux Brigitte , Cardarelli Pina 
Published: February 2011

Abstract
CD22 is a well-validated target for immunotherapy on B cell tumors. CD22 is a B lymphoid lineage-specific differentiation antigen, and its cell surface expression coincides with IgD expression in human. CD22 expression is upregulated on mature B cells, and is lost upon terminal differentiation to plasma cells. CD22 is also highly expressed on B cell tumors including non-Hodgkin's lymphoma (NHL) and acute lymphocytic leukemia (ALL). Antibodies to CD22 rapidly internalize, making it an ideal target for an antibody drug conjugate (ADC) therapeutic approach. Human antibodies to CD22 have been generated. The antibodies bind B cells with high affinity and are rapidly internalized upon binding. Anti-CD22 conjugates linked to highly potent synthetic DNA minor-groove binding alkylating (MGBA) agents have been prepared and tested in vivo for the treatment of established Ramos and Raji subcutaneous tumor xenografts. Anti-tumor efficacy of the anti-CD22 conjugate was highly specific in comparison with the isotype control conjugate. The anti-CD22 conjugate at a single dose of 0.3 µmole/kg resulted in regression of established subcutaneous tumors with less than 5% body weight loss and no clinical signs of toxicity. The anti-CD22 conjugate at a single dose of 0.1 µmole/kg was more efficacious than Rituximab treatment on Ramos tumors. The anti-CD22 conjugate also had better tumor growth inhibition than an anti-CD19 conjugate. In summary, anti-CD22-ADCs have been prepared which show superior in vivo efficacy to Rituximab and to anti-CD19-ADCs.
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 2578.
Abstract 2583: LA480, a bivalent humanized c-Met monoclonal antibody, inhibits tumor growth without eliciting significant agonist activity
Authors: Zeng Wei , Wortinger Mark , Yang Wei Jennifer , Peek Victoria , Yan Lei , Lu Jirong , Chow Chi-Kin , Vaillancourt Peter , Davies Julian , Denning Irene , Weir Spring , McClure Don , Chintharlapalli Sudhakar , Liu Ling 
Published: February 2011

Abstract
The receptor tyrosine kinase c-Met and its ligand HGF elicit multiple cellular activities including cell proliferation, motility, invasion, tubulogenesis, angiogenesis and anti-apoptosis. Dysregulation of this pathway has emerged as a crucial feature for many human tumors. However, past efforts in developing c-Met therapeutic antibodies that inhibit both ligand-dependent and ligand-independent c-Met activation have been largely unsuccessful due to agonist properties of the antibodies. In fact, c-Met antibodies exhibiting medium to strong agonist activity stimulate proliferation of both normal and tumor cells. We report here that LA480, a bivalent humanized monoclonal c-Met antibody, blocks HGF binding to c-Met and also induces c-Met internalization. Moreover, LA480 inhibits growth of xenograft tumors mediated by HGF-dependent and HGF-independent c-Met pathway activation. In order to evaluate whether LA480 has agonist activity, we tested LA480 in the following HGF-responsive biological assays: proliferation of primary human hepatocytes and tumor cell lines, scattering of DU145 cells, stimulation of HepG2 invasion and tubulogenesis, tube formation in endothelial and stromal cell co-cultures, and protection from apoptosis induced by staurospor in Caki-1 cells. A bivalent c-Met agonist antibody and HGF were included in the assays as positive controls, in addition to antibody isotype negative controls. Our results demonstrate that LA480 does not significantly stimulate cell proliferation, scattering, invasion, tubulogenesis, angiogenesis or apoptosis protection in the above assay systems. Under the same conditions, the agonist positive control c-Met antibody and HGF both significantly induced these biological effects. These unique properties of LA480 suggest that it may be a promising therapeutic reagent for treatment of cancers driven by ligand-dependent and ligand-independent c-Met activation.
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 2583.
Abstract 2602: The cardiotoxicity and myocyte damage caused by small molecule anticancer tyrosine kinase inhibitors is correlated with lack of target specificity
Authors: Hasinoff Brian B. , Patel Daywin 
Published: February 2011

Abstract
The use of the new anticancer tyrosine kinase inhibitors (TKI) has revolutionized the treatment of certain cancers. However, the use of some of these results in cardiotoxicity. Large scale profiling data recently made available for the binding of 7 of the 9 FDA-approved tyrosine kinase inhibitors to a panel of 317 kinases has allowed us to correlate kinase inhibitor binding selectivity scores with TKI-induced damage to neonatal rat cardiac myocytes. The 7 TKIs that were the subject of this study were: imatinib (Gleevec), sunitinib (Sutent), dasatinib (Sprycel), sorafenib (Nexavar), lapatinib (Tykerb), gefitinib (Iressa), and erlotinib (Tarceva). The tyrosine kinase selectivity scores, but not the serine-threonine kinase scores, were highly correlated with the myocyte damaging effects of the TKIs. Additionally, we showed that damage to myocytes gave a good rank order correlation with clinical cardiotoxicity. Finally, strength of TKI binding to colony stimulating factor 1 receptor (CSF1R) was highly correlated with myocyte damage, thus possibly implicating this kinase in contributing to TKI-induced cardiotoxicity. Support: CIHR and a Canada Research Chair in Drug Development to BBH.
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 2602.
Abstract 261: Epidermal growth factor receptor (EGFR)-mediated upregulation of matrix metalloproteinase-1(MMP-1) in glioblastoma cell lines involves multiple signaling pathways
Authors: Anand Monika , Zehner Zendra E. , Fillmore Helen L. 
Published: February 2011

Abstract
Glioblastoma Multiforme (GBM) is a devastating disease with an extremely poor prognosis primarily due to its invasive and infiltrative nature. Matrix metalloproteinases (MMPs) are important enzymes that regulate tumor microenvironment, alter cellular behavior and increase invasion and metastasis in wide variety of cancers. Previous studies from our laboratory have shown that MMP-1 is over expressed in GBM tissue and can influence glioma cell invasion in vitro. Since the epidermal growth factor receptor (EGFR) is amplified in human GBM, we wanted to determine the effect of EGFR activation by epidermal growth factor (EGF) on MMP-1 expression and invasion in human glioma cell lines and if so, determine the signaling mechanisms responsible for this induction. We stimulated glioma cell lines (T98 and U87) with EGF in the presence and absence of the EGFR inhibitor, AG1478. Inhibitors to multiple signaling pathways activated by EGFR induction were also used. All inhibitors tested were added to cells for 2 hrs prior to addition of EGF. In addition, transfections using AKT and STAT3 siRNA were conducted. Western Blotting was performed to examine the levels of MMP-1, EGFR, AKT, STAT3 and ERK. We observed that with EGF treatment, in addition to EGFR activation, AKT was phosphorylated, MMP-1 was induced and that in the presence of AG1478, AKT and EGFR phosphorylation was inhibited in a dose dependent manner. Importantly, MMP-1 up-regulation by EGF was abrogated in cells pretreated with AG1478. EGFR has been shown to up-regulate MAPK, PI3K and STAT3 pathways in glioma and other malignancies. Involvement of the MAPK pathway in the EGFR- mediated induction of MMP-1 was examined using the MAPK inhibitor, U0126. Only a modest decrease in MMP-1 levels was observed following treatment with EGF and U0126, suggesting potential inputs from other signaling pathways. Although there was a modest inhibition of AKT protein levels in cells treated with AKT siRNA, the levels of MMP-1 in these cells were significantly reduced. Current experiments focus on the role of AKT/PI3K and STAT3 signaling pathways in MMP-1 mediated glioma cell invasion.
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 261.
Abstract 2613: Assessment of pharmacokinetics-pharmacodynamics and antitumor activities of hydroxamate- and mercaptoacetamide-based histone deacetylase inhibitors
Authors: Konsoula Zacharoula , Velena Alfredo , Cao Hong , Jung Mira Oh 
Published: February 2011

Abstract
Structurally diverse histone deacetylase inhibitors (HDACIs) have emerged as chemotherapeutic agents and have shown to cause differentiation, cell cycle arrest and apoptosis. As an initial step in identifying a clinically applicable HDACI, we evaluated the in vitro and the in vivo properties of two mercaptoacetamide (6MAQH and 5MABMA) and a hydroxamate (H6CAHA)-based HDACIs: 1) The growth inhibitory activities of these inhibitors were evaluated and compared against a subset of prostate cancer and non-malignant epithelial cell lines. 2) The in vitro permeability, solubility and lipophilicity properties of the HDACIs were assessed. 3) In vivo, the antitumor activities were determined following i.p. administration of the inhibitors (0.4 mg/Kg) using mice bearing PC3 tumor xenografts (n = 10). 4) The plasma pharmacokinetics of the HDACIs and their effect on the acetylation of histone H4 in tissues were determined in nude mice. The data demonstrated that mercaptoacetamides preferentially inhibited the growth of cancer than nonmalignant cells, whereas the hydroxamate showed toxicity at higher concentrations in both cancer and normal cells. The mercaptoacetamides also conferred higher solubility under the acidic environment of the stomach (pH 1.2) and lower under the neutral of the small intestine (pH 7.4) than the hydroxamate. All the HDACIs exhibited high permeability as well as lipophilicity values. In vivo, HDACIs treatment led to tumor growth inhibition (p &lt; 0.001), which was sustained for at least 60 days. Plasma pharmacokinetics revealed that the area under the curve (AUC) was 8.08 ± 0.91 μM x h for H6CAHA, 4.97 ± 0.6 μM x h for 6MAQH μM x h, and 4.23 ± 0.43 μM x h for 5MABMA. The plasma half- lives for H6CAHA, 6MAQH and 5MABMA were 11.17 ± 0.87, 2.2 ± 0.33 and 1.98 ± 0.21 h, respectively. Taken together, these results provide support that the HDACIs target prostate cancer cells effectively, as evidenced by growth suppression in vitro and tumor growth inhibition in vivo. The mercaptoacetamide HDACIs preferentially inhibit the growth of cancer cells while exert limited effect on nonmalignant cells. However, the hydroxamate based HDACI exhibited superior in vivo pharmacological properties. Furthermore, the physicochemical and pharmacological characteristics of HDACIs provide a rationale for their further investigation as potent anticancer agents.
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 2613.
Abstract 2614: Anti-tumor efficacy and pharmacokinetics of the novel aptamer AS1411 in a continuous infusion nude rat xenograft model
Authors: Green Colin , Djeha Hakim , Bestwick Michael , Dobinson Donna , McLaughlin Fiona 
Published: February 2011

Abstract
AS1411 is a novel DNA aptamer that binds to the multi-functional protein nucleolin and induces cell death. AS1411 has shown activity at two different doses in combination with cytarabine in a phase II study of patients with AML.
We have previously shown that AS1411 has activity against a range of solid and hematological cancer cell lines, with IC50 values between 1 and 10 μM, when cells are exposed to AS1411 continuously for more than 3 days. We have also demonstrated efficacy in vivo in both lung (A549) and renal (A498) mouse xenografts. However, it has been challenging to provide optimal continuous dosing of AS1411 in mice; use of osmotic pumps or intraperitoneal bolus injection have been associated with low drug exposure. In the current study, we optimized the continuous infusion model by using nude, athymic rats with a surgically implanted catheter in a two-cycle xenograft study. Plasma and tumor samples were collected for PK determination, allowing a correlation of PK with efficacy.
The colorectal cell line HT29, which is sensitive to AS1411 in vitro, was used in this study. Cells (5×106) were implanted subcutaneously in the flank of female nude rats and tumors were allowed to grow to approximately 200 − 300 mm3 before surgical cannulation of the femoral vein. Following recovery, animals received AS1411 at 40, 80 or 180 mg/kg/day for two 7 day cycles of continuous infusion, 7 days apart. A vehicle control group received saline.
Animals in the 80 and 180 mg/kg/day groups exhibited a significant (p&lt;0.01) reduction in tumor volume compared to control animals at day 33 and at day 22 (interim analysis); this was not observed for animals in the 40mg/kg/day group (40mg kg/day in this model does not directly correlate to the clinical dose of the same name). AS1411 was well-tolerated by all animals in all dose groups.
Plasma levels of AS1411 were measured at the three dose levels after one cycle of treatment. Mean AS1411 plasma concentrations were 0.7, 2.5 and 5.0 μM, for rats treated at 40, 80 and 180 mg/kg/day, respectively. The plasma concentrations in the two higher dose groups are within the range of the in vitro IC50 concentrations of a panel of cell lines.
We conclude that AS1411 shows activity in vivo in the HT29 nude rat xenograft model. Doses associated with significant reductions in tumor volume were those that produced plasma concentrations close to the IC50 level for AS1411. This correlation has been used in planning further clinical development of AS1411, including a phase IIb study of patients with AML.
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 2614.