bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 678: Study of 2, 9-disecbutyl-1, 10-phenanthroline as a novel anticancer agent
Authors: Wang Dongsheng , Amin A.R.M. Ruhul , Peng Shifang , Sanghvi Chinar , Shin Dong M. , Eichler Jack F. 
Published: June 2012

Abstract
Development of new, safe, and effective drugs or strategies targeting molecular events and pathways which are responsible for cancer initiation and progression is an urgent need to improve cancer patient care. In this study, we tested the antitumor effect of a novel agent, 2, 9-disecbutyl-1, 10-phenanthroline (dsBPT), a 1, 10-phenanthroline derivative. Both in vitro cell line and in vivo xenograft models were applied to study the antitumor efficacy and underlying mechanism of this compound. IC50s were initially determined using lung cancer cell lines: A549 (0.25 μM) and H1703 (0.1 μM), head and neck cancer cell lines: TU686 (0.08 μM) and TU212 (0.2 μM), and normal bronchial epithelial cells: BEAS-2B (2.0 μM), indicating that the growth inhibitory effect of dsBPT on cancer cell lines was about 10 times greater than that on normal human epithelial cells. Further studies demonstrated that dsBPT at a concentration of 1-2 μM induced autophagy and G1 cell cycle arrest. At higher doses between 4-8 μM, the compound further induced apoptosis (40-80%). Combination of dsBPT with the cytotoxic agent cisplatin synergistically inhibited cancer cell growth (combination index = 0.3) and induced apoptosis (80-90%) at a concentration of 1 μM for each drug. Two experiments were then performed to test dsBPT in vivo. First, xenografted mice implanted with TU212 cells were treated with three drug doses (2mg/kg, 5mg/kg, 10mg/kg). Compound was given by IV injection once per week for 3 weeks. We found that 10 mg/kg treatment significantly reduced tumor growth as compared with the control group (p = 0.004). Under the same treatment schedule, further study showed that the combination of dsBPT (2 mg/kg) with cisplatin (2 mg/kg) significantly reduced the tumor volume as compared with the untreated control (p = 0.0017), while each of the single drugs at the same concentration showed no significant inhibitory effect on tumor growth (p = 0.10 and 0.15 for cisplatin and dsBPT, respectively). Neither significant weight loss nor major organ damage was observed by histology examination in the experimental animals in this study. In summary, our study suggests that dsBPT is a novel, highly potent antitumor drug that warrants further preclinical and clinical development either as a single agent or in combination with known chemotherapy drugs such as cisplatin. (This study is supported by grants from DOD W81XWH-07-1-0306 Project 5, and GCC Distinguished Scholar Award to ZC).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 678. doi:10.1158/1538-7445.AM2011-678
Abstract 702: Drug resistance and invasion in diffuse large B-cell lymphoma are mediated by Akt, 14-3-3ζ, and Vimentin
Authors: Cherry Evan M. , Bayless Kayla J. , Maxwell Steve A. 
Published: June 2012

Abstract
Acquired multi-drug resistance to the anthracycline-based CHOP chemotherapy is a major cause of unsuccessful treatment and mortality in 40% of diffuse large B-cell lymphoma (DLBCL) patients. To investigate molecular mechanisms of multidrug resistance, we generated CHOP-resistant DLBCL cells through repeated selection in the presence of a clinically-relevant CHOP cocktail (cyclophosphamide, doxorubicin, vincristine, prednisone at the ratio of 80:5.5:0.16:11.1). Differential protein expression between CHOP-sensitive and CHOP-resistant DLBCL cells was investigated by two-dimensional differential in-gel (DIGE) analysis, which identified 10 differentially-expressed proteins related to glycolysis (Triosephosphate isomerase-1, Enolase-1), cytoskeletal structure (Ezrin, Vimentin, Tubulin-specific chaperone B), purine biosynthesis (Serine hydroxymethyltransferase), calcium-binding (Sorcin), and apoptosis (p53, 14-3-3zeta, Akt). Upregulation of Akt, 14-3-3ζ, and Vimentin was observed by Western blotting in CHOP-resistant cells compared to CHOP-sensitive cells. These proteins were also heterogenously upregulated in primary DLBCL tissues relative to normal lymphatic tissue. Our previous studies showed that siRNA-mediated knockdown of 14-3-3ζ reversed CHOP resistance in DLBCL cells (Maxwell et al [2009] J. Biol. Chem. 284:22379-89). Our current study showed that chemical Akt inhibition overcame CHOP resistance in DLBCL cells and CHOP-resistant cells exhibited a five-fold greater ability to invade collagen matrices than CHOP-sensitive cells. Moreover, knockdown of Vimentin by siRNA or inhibition by Withaferin A decreased invasion capacity of the CHOP-resistant cells in collagen matrices. The data indicate activation of an Akt-14-3-3ζ-mediated signaling pathway as a contributor to the multi-drug resistant phenotype associated with vimentin-dependent invasive behavior in DLBCL cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 702. doi:10.1158/1538-7445.AM2011-702
Abstract 716: O6-Methylguanine DNA methyl transferase (MGMT) and tamoxifen resistance in patients with breast cancer
Authors: Konduri Santhi D. , Maddipatla Sreeram , Smith Joshua , Isley Beth , Caparas Maria-Lourdes M. , Constantino Susan M. , Shah Nikita , Baidas Said 
Published: June 2012

Abstract
Tamoxifen is an estrogen receptor antagonist in breast tissue. It has been used as a hormonal therapy for early and advanced breast cancer both in premenopausal and postmenopausal patients with estrogen receptor positive breast cancer. Acquired resistance to tamoxifen therapy is a common therapeutic encounter. Different mechanisms for Tamoxifen resistance have been postulated. In the present study we investigated if over expression of MGMT causes tamoxifen resistance in breast cancer patients.
Purpose: We sought to determine MGMT expression levels in various breast cancer cell lines as well as in breast cancer patient's samples before and after treatment with tamoxifen.
Experimental Design: MGMT expression levels were compared in breast cancer tissue samples obtained from patients before starting treatment with Tamoxifen and after tumor progression due to development of Tamoxifen resistance. MGMT expression level was evaluated using western blot and immunohistochemical assays. Several commercial breast cell lines were evaluated for expression of MGMT.
Results: We found that MGMT is over expressed in the majority of breast cancer cell lines compared to normal breast epithelial cells. Compared to pre Tamoxifen treatment, post Tamoxifen treated breast cancer patient samples have significantly higher levels of MGMT expression.
Conclusion: Collectively, our results demonstrate that breast cancer cells showed significantly higher levels of MGMT expression and furthermore, Tamoxifen treatment induces further MGMT over expression in breast cancer patients. According to our results over expression of MGMT is a possible cause for Tamoxifen resistance. Inhibition of MGMT might overcome Tamoxifen resistance and restore breast cancer sensitivity to Tamoxifen treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 716. doi:10.1158/1538-7445.AM2011-716
Abstract 739: Small molecule inhibitor, PZ39C8, promotes BCRP degradation via binding to TM5-loop-TM6
Authors: Qi Jing , Mo Wei , Dong Zizheng , Peng Hui , Zhang Jian-Ting 
Published: June 2012

Abstract
Multidrug resistance (MDR) and existing cancer stem cells (CSCs) are two major problems in successful treatment of cancers. Expression of breast cancer resistance protein (BCRP) is known to associate with both MDR and CSCs, suggesting that BCRP is an interesting and ideal target for development of chemosensitizing agents for better treatment of drug resistant cancers and elimination of CSCs. Recently, we identified a novel BCRP inhibitor PZ39 and its analogue compound PZ39C8 which are capable of inhibiting BCRP function and inducing BCRP degradation in lysosome. In the present study, we (1) investigated the mechanism of inhibitor-induced BCRP degradation using a stable cell line expressing GFP-BCRP in combination with pharmacological agents of endocytosis and trafficking and (2) determined the inhibitor binding site in BCRP using compound-conjugated Sepharose 4B beads and pull-down assay. We found that (1) the lysosomal inhibitor Bafilomycin A but not the proteosome inhibitor MG132 abolished PZ39C8-induced BCRP degradation; (2) dynasore, a potent endocytosis inhibitor, and 3-Methyladenine, a autophagy inhibitor, both efficiently blocked the PZ39C8-induced BCRP degradation from plasma and internal membranes; (3) following co-treatment with PZ-39C8 and endocytosis, trafficking, and lysosome inhibitors, BCRP co-localized with the LAMP-1, LC3II and Clathrin, EEA1, the markers of Lysosome, autophagy and endocytic pathways, respectively; and (4) PZ39C8 directly binds BCRP and the binding site/s appears to locate in the domain including TM5-loop-TM6. Taken together, we conclude that PZ39C8 binds to TM5-ECL3-TM6 of BCRP and induces BCRP degradation in lysosome via endocytic and autophagic dependent pathways. Thus, PZ39C8 is potentially a valuable probe for structure-function studies of BCRP and a lead compound for developing therapeutics targeting BCRP-mediated MDR in combinational cancer chemotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 739. doi:10.1158/1538-7445.AM2011-739
Abstract 74: Genome-wide DNA methylation analysis of pT1a renal cell carcinoma and renal oncocytomas
Authors: Ibragimova Ilsiya , Banumathy Gowrishankar , Al-Saleem Tahseen , Uzzo Robert G. , Cairns Paul 
Published: June 2012

Abstract
Nephron sparing surgery (partial nephrectomy) is currently performed on small renal masses (4cm or less in size) confined to the kidney (pT1a). Up to 25% of small renal masses are benign, the majority being oncocytomas. Benign oncocytomas lack distinct radiographic findings on computerized tomography (CT) and cannot be diagnosed accurately using imaging alone. No difference in tumor size at presentation or tumor growth rate was noted between oncocytoma and RCC in a review of the literature. A needle biopsy or non-invasive urine based differential diagnosis of a benign lesion potentially would allow patients with equivocal renal lesions to avoid unnecessary surgery as well as anxiety if under active surveillance.
The epigenetic alteration of aberrant DNA methylation has potential benefits as a choice of a biomarker because aberrant methylation occurs frequently and early in tumorgenesis and can be detected at extremely sensitive and specific levels by currently available technology. It is known that aberrant hypermethylation of the VHL gene occurs in a subset of clear cell RCC but is absent in oncocytoma. We hypothesized that additonal genes with a differential methylation status between benign oncocytoma and RCC could be identified.
In this study, we performed genome-wide detection of DNA methylation in 25 RCC (pT1a), 25 oncocytomas of 4cm or less in size, and 4 age-matched histologically normal kidney tissues using the Infinium HumanMethylation27 BeadChip. To date, we have evidence that the profile of aberrant gene methylation is different between benign and malignant small renal masses matched for median size. Infinium-identified differentially methylated genes are validated using direct bisulfite sequencing, then a qMSP assay designed. If the panel of differentially methylated genes we have identified are verified in an independent set of small renal masses, we can then determine the predictive value of methylation-based detection of benign oncocytoma versus malignant RCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 74. doi:10.1158/1538-7445.AM2011-74
Abstract 744: PEDF silencing a novel mechanism of antihormone resistance in breast cancer
Authors: Lewis-Wambi Joan S. , Huang Min 
Published: June 2012

Abstract
Despite the benefits of endocrine therapies in treating estrogen receptor alpha (ERα)-positive breast cancer, many tumors eventually become resistant. Identifying the underlying cellular and molecular mechanisms responsible for endocrine resistance remains a critical and immediate need. Pigment epithelium-derived factor (PEDF) is a multifunctional protein released by adipocytes and increased in metabolic syndrome and insulin-resistance. Moreover, PEDF belongs to the serine protease inhibitor family but does not inhibit proteases. It is a potent endogenous inhibitor of angiogenesis and a promising agent for diabetic retinopathy and potentially cancer. Previous studies have shown that PEDF expression is significantly reduced in breast cancer cells (compared to normal breast epithelium) and its reduction is associated with disease differentiation (lowest levels in poorly differentiated tumors), disease progression and poor patient outcome, however, it is not known whether PEDF plays a role in endocrine resistance. In the present study, we evaluated PEDF expression in endocrine-sensitive MCF-7, T47D, and ZR-75-1 breast cancer cells versus endocrine resistant MCF-7:5C, MCF-7:2A, and BT474 cells and found that PEDF mRNA and protein levels were dramatically reduced in the latter group of cells. In addition, tissue microarray analysis of primary tumors from patients (N=66) who subsequently developed invasive recurrence after adjuvant tamoxifen treatment revealed that expression of PEDF protein was reduced by 45% and loss of PEDF was associated with enhanced expression of phosphoSer167ERα and the receptor tyrosine kinase RET (Rearranged during Transfection). Importantly, we found that silencing endogenous PEDF in tamoxifen-sensitive MCF-7 and T47D breast cancer cells abolished their sensitivity to the inhibitory effects of tamoxifen whereas reexpression of PEDF in endocrine resistant MCF-7:5C and MCF-7:2A cells restored their sensitivity to tamoxifen and raloxifene. Furthermore, we found that reexpression of PEDF in endocrine-resistant cells significantly reduced the levels of RET, cyclin D1 and phospho-AKT, in these cells. Together, these findings suggest that PEDF silencing might be a novel mechanism for the development of endocrine resistance in breast cancer and that PEDF expression could be used as a predictive marker of endocrine sensitivity. Furthermore, these findings suggest that recombinant PEDF might be beneficial in treating patients with antihormone resistant disease with potential application in ER-negative disease.
This work was supported by the NIH Career Development Grant K01CA120051 01A2 and the Hollenbach Family Fund (JLW).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 744. doi:10.1158/1538-7445.AM2011-744
Abstract 754: Heat shock protein vaccines for immunotherapy ofHer-2/neu positive breast cancers
Authors: Smith Annalise , Lopez Rodriguez Darlah M. , Podack Eckhard R. , Andreansky Samita S. 
Published: June 2012

Abstract
Over-expression of Her-2/neu protein, a member of the epidermal growth factor receptor (EGFR) involved in cell growth results in cancer development. 20-30% of breast cancers over-express Her-2/neu protein and this has been correlated with poor prognosis, leading to recurrence after their initial treatment. Thus new strategies are necessary to combat this devastating disease. The selective expression of HER-2/neu in epithelial carcinogenesis makes HER-2/neu antigen an ideal target for immunotherapy. The objective of our research is to explore vaccine strategies that impacts both B and T cell responses in HER-2/neu breast cancer models. We are exploring heat shock proteins (HSP) vaccines that will chaperone tumor-associated antigens including our antigen of interest Her-2/neu protein to elicit innate and adaptive responses. We are utilizing the rat Her-2/neu as our model antigen and are administering these vaccines in transplantable and transgenic her-2/neu murine models after tumor implantation. Our first approach was to generate a Her-2/neu derived HSP gp96 in a secretable form. It has been reported that gp96 can ubiquitously bind to cell associated peptides and cross present these antigens to CD8+ T-cells to generate an effective cytotoxic T cell (CTL) response. Cancer cells expressing rat Her-2/neu were stably transfected with a mouse gp96IgG eukaryotic expression vector, where the endoplasmic retention signal sequence KDEL of gp96 was replaced with the hinge and CH2 and CH3 domains of murine IgG1. 2×104 stably transfected cells secreted within 24h 100- 200ng gp96IgG. Our goal is to generate Her-2/neu specific CD8 T cell responses that would result in vivo tumor delay. Our second approach was to test the adjuvanticity of a mixture of HSPs in combination with irradiated tumor cells. Administration of the vaccine in a therapeutic setting not only delayed tumor growth, but also provided survival benefit. Additionally, vaccinated animals were superior in eliciting Her-2/neu specific antibody response when compared to the HSP vaccine or the irradiated tumor cells alone. Our long-term goal is to combine both approaches to enhance cytotoxic T cell (CTL) and B cell specific response against Her-2/neu specific cancers. Funded by: American Cancer Society MRSG# 08-064-01-LIB and Women's Cancer Association
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 754. doi:10.1158/1538-7445.AM2011-754
Abstract 755: Dendritic-cell vaccine: Cross-presentation of carcinoembryonic antigen (CEA) by dendritic cells (DCs) through a fusion protein targeting CD74 on DCs
Authors: Chen Xiaochuan , Chang Chien-Hsing , Stein Rhona , Goldenberg David M. 
Published: June 2012

Abstract
Milatuzumab (hLL1, Immunomedics, Inc.) is a humanized anti-CD74 monoclonal IgG1 antibody (mAb) currently in phase I-II clinical trials as a therapeutic mAb for CD74-expressing non-Hodgkin lymphoma, chronic lymphocytic leukemia, and multiple myeloma. Since CD74 is also expressed by normal antigen-presenting cells (APCs), including DCs, we investigated the potential application of the Fab fragment of hLL1 as a novel targeting vector in a cancer vaccine.
Methods: A fusion protein, hLL1-Fab-A3B3, was constructed by fusing the Fab fragment of milatuzumab to the A3B3 domain of CEA. The binding profiles and cytotoxic potenial of hLL1-Fab-A3B3 on APC subsets in human peripheral blood mononuclear cells (PBMCs) were assessed by flow cytometry; the impact of hLL1-Fab-A3B3 on APC function was assessed by allogeneic mixed leukocyte reaction (MLR) through CFSE-based cell proliferation assay. The cross-presentation of CEA by DCs was evaluated by three rounds of weekly stimulation of autologous T cells with DCs loaded with hLL1-Fab-A3B3 or CEA protein, followed by measuring CEA-specific CD8+ T cells with HLA-A*0201-restricted CAP-1 pentamer (YLSGANLNL).
Results: Both bivalent milatuzumab and monvalent hLL1-Fab-A3B3 bound efficiently to human APC subsets, which include BDCA-1+ myeloid DCs type 1 (mDC1), BDCA-2+ plasmacytoid DCs (pDCs), BDCA-3+ myeloid DCs type 2 (mDC2), B lymphocytes, and monocytes, but neither of the two bound to T cells. While milatuzumab selectively reduced mDC1 (by 60.8%, P=0.003, n=6 donors) and mDC2 (by 53.8%, P=0.0026, n=7 donors) in PBMCs, presumably mediated by the presence of Fc, or a necessity for divalent milatuzumab binding, hLL1-Fab-A3B3 did not have this effect, nor did it affect the viability of T cells and other APC subsets (pDCs, monocytes, and B cells). The allogeneic MLR was significantly inhibited by milatuzumab (P&lt;0.0001), but not by hLL1-Fab-A3B3 treatment (P=0.6644). After three rounds of weekly stimulation of autologous T cells, DCs loaded with hLL1-Fab-A3B3 were more efficient in inducing CEA-specific CD8+ T cells than DCs loaded with CEA, suggesting that the hLL1-Fab enhances the cross-presentation of CEA by DCs.
Conclusion: hLL1-Fab is a promising, novel targeting antibody for use as a cancer vaccine, because it enhances the cross-presentation of antigens without significant cytotoxicity and functional alteration on APCs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 755. doi:10.1158/1538-7445.AM2011-755