bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 681: Knockdown of connective tissue growth factor and treatment with temozolomide inhibited invasion, angiogenesis, and tumorigenesis of human glioblastomas
Authors: George Joseph , Banik Naren L. , Ray Swapan K. 
Published: February 2011

Abstract
Connective tissue growth factor (CTGF) is a putative proto-oncogene and plays a crucial role in endothelial cell migration and tumor angiogenesis. CTGF is highly upregulated in proliferating endothelial cells and glioblastoma cells. In this investigation, we examined whether knockdown of CTGF at the mRNA level and treatment with temozolomide (TMZ) could inhibit cell invasion, angiogenesis, and growth of human glioblastoma SNB-19 and T98G cells in vivo. The cells were stably transfected with a plasmid vector carrying the human CTGF siRNA cDNA and then treated with 10 μM TMZ for 48 h. Semiquantitative PCR, Western blotting, and immunohistochemical staining demonstrated 80% downregulation of CTGF both at mRNA and protein levels after stable transfection. Matrigel invasion, cell migration from spheroids, and cell proliferation studies demonstrated significant inhibition of cell invasion, migration, and proliferation, respectively, of both cell lines after downregulation of CTGF and treatment with TMZ. In vitro and in vivo angiogenesis assays demonstrated inhibition of network formation of endothelial cells and neovascularization under the dorsal skin of nude mice, respectively, after knockdown of CTGF and treatment with TMZ. Both subcutaneous and intracerebral tumorigenesis in nude mice was markedly reduced in CTGF downregulated cells after TMZ treatment. Mechanistic studies demonstrated significant reduction of PCNA, VEGF, c-Myc, CDK2, CDK4, and cyclin D1 and upregulation of the cell cycle inhibitors p21Waf1 and p27Kip1. Flow cytometric analysis showed cell cycle arrest at G2/M phase in both cell lines after CTGF knockdown and TMZ treatment. Taken together, our study indicates that the CTGF knockdown and TMZ treatment effectively prevents cell invasion, migration, angiogenesis, and growth of glioblastomas in vivo. Therefore, CTGF knockdown during TMZ treatment offers a novel and potential therapeutic strategy for controlling the growth of glioblastomas. This investigation was supported in part by the R01 grants (CA-91460 and NS-57811) from the National Institutes of Health (Bethesda, MD).
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 681.
Abstract 683: Evaluating the therapeutic potential of a peptide derivative of cancer-associated PCNA in DNA repair deficient breast cancers
Authors: Phipps Elizabeth A. , Dobrolecki Lacey E. , Hickey Robert J. , Sledge George W. , Herbert Brittney-Shea , Malkas Linda H. 
Published: February 2011

Abstract
Our laboratory was the first to isolate and purify an intact mammalian cell multiprotein DNA replication complex, termed the synthesome, from a variety of human cell types that was both stable and fully functional. Subsequent work revealed that the synthesome of malignant breast epithelial cells exhibits a more error-prone synthesis process than that of nonmalignant breast epithelial cells. We recently correlated the low replication fidelity of malignant cells was due at least in part to a post-translational modification of a specific protein component of the synthesome: proliferating cell nuclear antigen, or PCNA. Our laboratory developed an antibody (cancer-associated or caPCNAab) specific to the cancer-associated PCNA isoform (cancer-associated or caPCNA), providing hope of an effective diagnostic marker of malignancy. Additionally, peptides were derived from the caPCNA sequence (caPeptides) and these peptides were shown to augment the action of doxorubicin (DOX) in leukemia cells while leaving nonmalignant cells intact. caPeptides may possess anti-cancer therapeutic potential through blocking the association of caPCNA with its binding partners involved in DNA replication and repair. The objective of this study was to determine the mechanism by which caPeptides directed against caPCNA induced cancer cell cytotoxicity. Breast cancer cells from a patient harboring a hereditary mutation in BRCA1, a major component of DNA double strand break repair (HCC1937 cells), were used in this study. As a genetically matched control, the wild-type breast cancer 1 early onset gene (BRCA1) was transduced into HCC1937 cells (referred to as HCC1937 + wild-type BRCA1). MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assays were conducted with caPeptides at a variety of timepoints both alone and in combination with DNA damaging agent cisplatin in HCC1937 and HCC1937 + wild-type BRCA1 cells. The data suggests cells lacking wild-type BRCA1 show increased sensitivity to caPeptides in comparison to isogenic controls transduced with wild-type BRCA1. We show that caPeptides augment the action of DNA damaging agent cisplatin. Furthermore, caPeptides containing amino acid substitutions in specific sites within the peptide show enhanced cytotoxicity over wild-type caPeptides. This work may provide information useful in a clinical setting as caPeptides could benefit a particular subset of breast cancer patients. Additionally, caPeptide studies may shed light on the deregulated replication and repair processes common in 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 683.
Abstract 686: Potentiation of the cytocidal effect of streptozotocin on carcinoid neuroendocrine cells by a pharmacological inhibitor of poly(ADP-ribose) polymerase
Authors: Richard Véronique , Shah Girish M. 
Published: February 2011

Abstract
Carcinoid neuroendocrine tumors (CNETs) are resistant to chemotherapy and the higher level doses of single or combination chemotherapy that are effective against these cancers also cause significant side-effects to the surrounding healthy tissues; therefore it is necessary to potentiate chemotherapy of these cancers. In the advanced clinical trials for different cancers, the pharmacological inhibitors of the DNA damage-responsive nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1 or PARP) have shown a significant promise either as monotherapy or as potentiators of other chemotherapeutic agents. Here, we examined whether PARP-inhibitor PJ-34 can potentiate the therapy of CNETs by streptozotocin (STZ), because STZ causes DNA damage that is repaired by base excision repair pathway in which PARP-1 is known to play a significant role. We used the CNDT2.5 as model NET cells to show that treatment of cells with 1 μM PJ-34 could effectively block the activation of PARP in response to 0.5 and 1 mg/ml STZ. We also show that lower dose of STZ (0.5 mg/ml), which had no impact on the viability or the clonogenicity of cells becomes cytocidal by co-treatment with PJ-34. The potentiation effect by PJ-34 was also seen at higher (1 mg/ml) doses of STZ. We are currently examining the mechanism of potentiation of STZ in NETs by PARP-inhibitors. In conclusion, our results demonstrate that PARP-inhibitor can significantly potentiate therapeutic efficacy of STZ against NETs, and thus add back the chemotherapy option against these cancers.
Acknowledgment: We are thankful to the Canadian Institutes of Health Research for the Banting & Best Graduate Scholarship to VR and the research grant support (Grant # MOP-89964) to GMS.
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 686.
Abstract 692: Antitumor activity of novel structure-based chemotherapeutic agent for the intervention of colorectal cancer
Authors: Jaiswal Aruna S. , Banerjee Sanjeev , Panda Harekrushna , Bulkin Charles D. , Izumi Tadahide , Sarkar Fazlul H. , Ostrov David A. , Narayan Satya 
Published: February 2011

Abstract
Colorectal cancer is the second most common cause of cancer-related death in both men and women in the Western hemisphere. The success of treatment of colon cancer patients depends on matching the most effective therapeutic regimen with the characteristics of the individual patient. The primary challenge in achieving this goal is the heterogeneity of the disease. In the past 10 years, the overall survival of colon cancer patients has significantly improved with adjuvant trials of drugs; the recurrence rate over 5 years is still high. Thus, there is clearly an urgent need for the development of new chemotherapeutic drugs and strategies. The recent emerging concept to sensitize cancer cells to DNA-alkylating drugs is by inhibiting various proteins in the base excision repair (BER) pathway. We used structure-based molecular docking of DNA polymerase β (Pol-β) and identified a potent small molecular weight inhibitor (SMI), NSC-666715. We determined the specificity of this SMI for Pol-β by using in vitro activities of APE1, Fen1, DNA ligase I, and Pol-β-directed single nucleotide (SN)- and long-patch (LP)-BER. The binding specificity of NSC-666715 with Pol-β was also determined by using fluorescence anisotropy. The effect of NSC-666715 on the cytotoxicity of the DNA-alkylating drug, Temozolomide (TMZ), to colon cancer cells was determined by in vitro clonogenic and in vivo xenograft assays. The reduction in tumor growth was higher in the combination treatment relative to untreated or monotherapy treatment. NSC-666715 showed a high specificity for blocking Pol-β activity. It blocked Pol-β-directed SN- and LP-BER without affecting the activity of APE1, Fen1 and DNA ligase I. Fluorescence anisotropy data suggested that NSC-666715 directly and specifically interacts with Pol-β and interferes with binding to damaged DNA. NSC-666715 drastically induces the sensitivity of TMZ to colon cancer cells both in vitro and in vivo assays. The results further suggest that the disruption of BER by NSC-666715 negates its contribution to drug-resistance and bypasses other resistance factors, such as mismatch repair defects. Our findings provide the “proof-of-concept” for the development of highly specific and thus safer structure-based inhibitors for the prevention of tumor progression and/or treatment of colorectal cancer. Funded by NCI-NIH grants CA-097031 and CA-100247 to S.N.
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 692.
Abstract 693: Histone deacetylase inhibitors attenuate epirubicin induced p53 expression
Authors: Thurn Kenneth T. , Thomas Scott , Miller Ashleigh , Munster Pamela 
Published: February 2011

Abstract
Preclinical and clinical studies have demonstrated that Histone Deacetylase Inhibitors (HDACIs) can act synergistically with topoisomerase II inhibitors (e.g. doxorubicin, epirubicin) to increase the induction of apoptosis in breast cancer cells. We have previously shown that HDACIs (i.e. valproic acid and suberoylanilide hydroxamic acid, SAHA/vorinostat) caused a reduction in the expression of specific chromatin maintenance genes including HP1-, DNMT1 and SMC1-5 with subsequent chromatin decondensation. Chromatin decondensation facilitates access for DNA damaging agents such, as topoisomerase inhibitors, to their DNA substrate resulting in an increase in the topoisomerase induced DNA strand breaks and cell death. Using siRNA mediated depletion of HDAC2, similar synergistic effects were observed compared to valproic acid or SAHA. This was not observed with depletion of HDAC1 or HDAC6. This suggested the specific role of HDAC2 in mediating the synergy in increased DNA damage and apoptosis with epirubicin.
However, efficient DNA strand break repair may be an alternate mechanism of resistance. To determine whether the HDAC inhibitors play a role in the inhibition of repair enzymes in addition to the increased induction of epirubicin induced strand breaks, we sought to determine the effects of HDACIs on epirubicin mediated DNA damage repair. Previous studies have shown that various HDACis down-regulate DNA repair associated genes including BRCA1, Ku70, and Rad51. Micro-array analysis performed by our group of cultured breast cancer cells treated with valproic acid or siRNA targeting HDAC2 revealed the down-regulation of the dsDNA repair genes Rad51b and Rad51c. These Rad51 paralogs have distinct functions in homologous recombination. Rad51b has been shown to associate with, and phosphorylate p53. Rad51c is able to exchange DNA strands vital for homologous recombination, and has been suggested to recruit Rad51 to sites of DNA damage. It is also suggested to be a Trp53-dependent tumor suppressor. We show that treatment of breast cancer cells with vorinostat caused a decrease in p53 protein expression. Furthermore, pre-treatment of these cells with valproic acid or SAHA significantly inhibited the induction of p53 in the presence of epirubicin. At the time points tested (0-120 minutes), this corresponded to an initial decrease in DNA repair kinetics as demonstrated by γ-H2AX expression. We hypothesize therefore that the treatment of breast cancer cells with HDACis in the presence of epirubicin results in a decreased expression of the homologous recombination Rad51 paralog proteins and downstream p53.
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 693.
Abstract 696: Anti-NRP1 tumor uptake is impacted by normal tissue sinks in a tumor bearing mouse model
Authors: Bumbaca Daniela , Boswell Charles A. , Xiang Hong , Port Ruediger , Schweiger Michelle , Stainton Shannon , Bagri Anil , Theil Frank-Peter , Fielder Paul J. , Khawli Leslie A. , Shen Ben-Quan 
Published: February 2011

Abstract
Neuropilin-1 (NRP1) is a VEGF165 and semaphorin receptor widely expressed by vascular endothelial cells in normal tissues and on some tumor cells. Blocking NRP1 with a human IgG1 against the b domain of NRP1 has been shown to inhibit tumor growth in several preclinical models. However, due to the wide expression of NRP1 in normal tissues, the uptake of anti-NRP1 by tumor cells may be impacted by the uptake in normal tissues. The objective of this study was to determine the normal tissue uptake of anti-NRP1 and assess its impact on tumor tissue uptake in a tumor bearing mouse model. Nude mice bearing tumors with either low, HM7, or high, SKMES, NRP1 expression were dosed with [111In]-DOTA labeled anti-NRP1 with or without excess amounts of unlabeled anti-NRP1 via single IV injection. Following dosing, blood, tumor, and several normal tissues were collected at pre-selected time points for the determination of radioactivity levels using a gamma counter. In the absence of unlabeled anti-NRP1, 3% Injected Dose (ID)/ml of radioactivity was observed in the blood at 15 minutes post-dose and decreased quickly. There was minimal radioactivity seen in tumor tissue. In contrast, the majority of radioactivity was detected in the lungs and liver. With increasing amount of unlabeled anti-NRP1, the radioactivity in the lungs/liver dropped, while increasing in blood and tumor tissue. At ∼10 mg/kg unlabeled anti-NRP1, there was no additional decrease of radioactivity in these normal tissues whereas the tumor radioactivity appeared to reach its peak. Taken together, these data suggest that the lungs/liver are tissue sinks that sequester a majority of the anti-NRP1 when given at lower doses, thus hampering tumor uptake. It is important to optimize the dose and dose regimen in order to overcome this tissue sink binding and allow for a sufficient amount of antibody to be available for tumor uptake.
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 696.
Abstract 697: Inhibition of Cancer Progression by Upregulation of the Opioid Growth Factor (OGF) - OGF Receptor (OGFr) Axis Using Imquimod or Low Dose Naltrexone
Authors: McLaughlin Patricia J. , Stucki Jaimon , Zagon Ian S. 
Published: February 2011

Abstract
Opioid growth factor (OGF, [Met5] enkephalin), is a tonically active, negative growth factor, and interacts with a nuclear-associated receptor, OGFr. The OGF-OGFr axis mediates cell proliferation by targeting cyclin-dependent kinase inhibitory pathways. Overexpression of OGFr by pharmacological modulation of several human cancer cell lines in tissue culture has been shown to result in decreased cell replication in response to either elevated endogenous OGF or exogenous administration of this inhibitory peptide. The present study examines tumor progression in nude mice whereby established tumors of human squamous cell carcinoma of the head and neck are treated by 2 methods of upregulation of the OGF-OGFr axis: imiquimod or low dosages of the opioid antagonist naltrexone (LDN; 0.1 mg/kg naltrexone). Tumor volume was monitored 3 times weekly. Some tumors were assessed for immunohistochemical levels of OGF and OGFr. Imiquimod, a promoter of OGFr gene activity, was administered topically either 1X or 3X each week. LDN was given systemically 1X or 3X per week, or daily. At the time of death, tumor volumes for the 1X and 3X imiquimod treated mice were 18 and 47%, respectively, smaller than controls, and tumor weights were decreased 36 and 43%, respectively relative to controls. All LDN treatment regimens effectively reduced tumor volume relative to mice receiving vehicle, with a regimen-related decrease in tumor growth noted throughout the study. At termination on day 35, mean tumor volumes of mice exposed to LDN were reduced from vehicle-treated controls by 35%, 61% and 84% when given 1X/week (p&lt;0.05), 3X/week (p&lt;0.001) and daily (p&lt;0.001), respectively. Tumor masses at the time of termination were 42%, 60%, and 89% smaller in the 1X/week, 3X/week, and daily, respectively, LDN treatment groups relative to controls. Semi-quantitative immunohistochemical analysis of OGF levels in tumor tissue revealed marked elevations of peptide following either imiquimod or LDN therapy. OGF tissue levels were elevated 70% and 95% in tissue from mice treated with 3X/week imiquimod or 3X/week LDN, respectively, relative to mice receiving vehicle. In summary, modulation of the OGF-OGFr axis provides new and novel therapeutic strategies for the treatment of human cancers.
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 697.
Abstract 701: Elevated insulin-like growth factor 1 receptor provides an essential survival signal via Bcl-xL in rhabdomyosarcoma cells as an alternative to Bcl-2 overexpression
Authors: Mayeenuddin Linnia H. , Yu Yunkai , Kang Zhigang , Helman Lee J. , Cao Liang 
Published: February 2011

Abstract
Insulin-like growth factors and their receptor IGF1R play important roles in growth, development, stress response, aging, and cancer. Many antibodies targeting IGF1R are in varies stages of clinical development. It is important to understand the mechanism of the antibody-mediated cancer cell growth inhibition and death, and to identify biomarkers predictive of responses that can be implemented in clinical investigations. We previously reported that IGF1R mediated cell growth suppression of rhabdomyosarcoma (RMS) in vitro and in vivo, in which the anti-proliferative activity was correlated with IGF1R levels and AKT signaling (Cao, et al., Cancer Research 2008, 68:8039). Here, we show that in some RMS cells, treatment with a humanized IGF1R antibody results in a rapid onset of mitochondrial-dependent apoptosis, including mitochondrial depolarization, cytochrome C release, and the activation of specific caspases. The antibody-induced cell death is mediated in part via AKT-dependent pathway, and both the inhibition of AKT signaling and induction of cell death by anti-IGF1R can be rescued by the introduction of a constitutively active AKT. Further analysis reveals IGF1R antibody-induced hypophosphorylation (activation) of BAD and the activation of downstream BAX. Bcl-xL was previously shown to be a key target of activated BAD. Our data indicate that cells with the transgenic expression of Bcl-xL are completely resistant to antibody-induced cell death, while still susceptible to antibody-mediated growth inhibition. Moreover, siRNA against Bcl-xL enhances anti-IGF1R-induced apoptosis. Interestingly, the examination of RMS cell lines and tumors reveals an inverse correlation between elevated IGF1R and another pro-survival gene Bcl-2 (P=0.033). Thus, our results indicate that RMS pathogenesis may involve two strategies for cell survival: 1) increasing IGF1R expression that enhances Bcl-xL activity; or 2) up-regulating Bcl-2 expression. Our study suggests a particular subgroup of the cancer with elevated IGF1R and low Bcl-2 maybe more susceptible to anti-IGF1R treatment.
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 701.
Abstract 704: Development of therapeutic antibodies targeting Notch3 in lung cancer
Authors: Lin Luping , Mernaugh Raymond , Carnahan Robert , Carbone David P. , Dang Thao P. 
Published: February 2011

Abstract
The Notch receptors are essential for both normal development and tumorigenesis in many human cancers. Notch3 is expressed in 40% of all lung cancers. Inhibiting this pathway results in reduced tumor growth in lung in vitro as well as in vivo. Thus, this pathway represents a potentially important target for therapeutic development. Here we report the early results of a strategy to inhibiting Notch3 signaling through the development of Notch3 monoclonal antibodies. Using a Notch3 peptide library, we discovered two regions of the extracellular domain, believed to be the binding regions for the Notch3 ligand, Jagged1. The recombinant proteins representing these two regions, respectively, were used as antigens to immunize mice. We demonstrated that antisera from these mice immunized with portions of the receptor extracellular domain can inhibit Notch3 activation. Further developments of hybridoma clones were screened with ELISA, immunoprecipitation and their ability to inhibit Notch3 cleavage. 12 hybridoma clones were selected, and 4 out of 12 antibodies with IgG1 or IgM isotypes were found to specifically inhibit Notch3 activation but not Notch1. Further testing is on going to validate these findings as well as to determine affinity and anti-tumor activity of these antibodies. Development of monoclonal antibody to specifically inhibit Notch3 ligand binding regions could serve as a strategy for the development of future therapeutics for patients with 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 704.