bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5286: Evaluation of 64Cu-labeled peptide for in vivo imaging of Thomsen-Friedenreich antigen expressing breast carcinomas
Authors: Kumar Senthil R. , Quinn Thomas , Deutscher Susan 
Published: June 2012

Abstract
Introduction: Thomsen-Friedenreich carbohydrate antigen (TF; Galβ1-3GalNAc) is displayed on cell surface proteins and lipids in ∼90% of adenocarcinomas including those of the breast. We investigated the ability of a peptide, DRD-IVWHRWYAWSPASRI-DRD-NH2 (TF-pep), selected through bacteriophage display to bind breast and prostate carcinoma cells expressing TF. It is hypothesized that TF-pep once radiolabeled with 64Cu, a positron radiation emitter, has the potential to be used as a positron emission tomography (PET) imaging agent for TF expressing breast tumors for diagnostic purposes.
Experimental Procedure: A bifunctional-chelator (1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)) was attached to the TF-pep with Gly-Ser-Gly (GSG) spacer. The peptide was radiolabeled with 64Cu in ammonium acetate buffer pH 6.8 at 80oC for 60 minutes. In vitro cell binding studies with both human breast (MDA-MB-435) carcinoma cells, as well as normal breast epithelial (184A1) cells were performed with the radiolabeled peptide. In vivo biodistribution and PET/CT imaging of the tumor with radiolabeled peptide was analyzed in SCID mice bearing MDA-MB-435 tumor xenografts. Results: 64Cu-NOTA-Gly-Ser-Gly-TF-pep peptide bound to human MDA-MB-435 carcinoma cells in a time dependant manner while insignificant binding was observed with normal breast 184A1 cells. In vivo biodistribution studies demonstrated radiolabeled peptide accumulation in MDA-MB-435 tumor-bearing SCID mice (∼1.09 ± 0.34 %, and 0.85 ± 0.06% ID/g in tumor) at 0.5 h and 2 h, respectively. Little accumulation occurred in other organs with the exception of liver (1.12 ± 0.12% ID/g, and kidneys (15.4 ± 1.2% ID/g) at 1 h. Live imaging studies with 64Cu-NOTA-Gly-Ser-Gly-TF-pep (300 μιχρoCi) demonstrated good tumor uptake after 1 h post-injection.
Conclusions: The TF-specific peptide once radiolabeled with 64Cu, can function as a non-invasive in vivo tumor imaging agent of human breast and other carcinomas expressing this antigen.
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 5286. doi:10.1158/1538-7445.AM2011-5286
Abstract 5311: The targeting effect of radio-labeled LXY1 and LXW7 against glioblastoma on xenograft mouse model
Authors: Xiao Wenwu , Liu Ruiwu , Yao Nianhuan , Lam Kit S. 
Published: June 2012

Abstract
Glioblastoma, the most common type of primary brain tumors in adults, remains largely incurable, and surgical resection followed by radiation and chemotherapy has been shown to only slightly increase patient survival. New approaches to treat this deadly cancer are needed. Small peptide-based compounds have attracted wide interest as cancer targeting agents for the delivery of radionuclides or cytotoxic drugs to tumors. Using the “one-bead-one-compound” (OBOC) combinatorial library method, we have identified a specific ligand, LXY1, which targets the α3β1 integrin on glioblastoma cell line U87MG. We have also discovered another novel ligand containing a RGD motif, LXW7, which targets the αvβ3 integrin of U87MG cells and tumor endothelial cells. LXY1 and LXW7 demonstrated excellent tumor targeting efficacy in in vivo optical imaging studies. To further investigate the targeting property of the peptides and precisely clarify their in vivo biodistribution profile, we have conjugated LXY1 and LXW7 to the metal chelator CB-TE2A complexed with 64Cu to perform PET imaging and biodistribution studies. The results indicate 64Cu-labeled LXY1-CB-TE2A conjugate efficiently targets both orthotopic and subcutaneous glioblastoma. The LXW7-CB-TE2A conjugate also demonstrates good tumor accumulation. Both conjugates show relatively rapid clearance from tumor site and high uptake in the liver and kidney beside to tumor. The undesired high uptake of the peptides in the liver and kidney indicate both peptides in current version may be more promising in radioimaging than radiotherapy for glioblastoma.
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 5311. doi:10.1158/1538-7445.AM2011-5311
Abstract 5359: Cytotoxicity of MLN8237 and SAHA in pediatric cancer cell lines
Authors: Muscal Jodi , Scorsone Kathy , Ecsedy Jeffrey , Berg Stacey 
Published: June 2012

Abstract
Purpose: Children with recurrent or refractory tumors often have a poor prognosis. Innovative drug combinations are necessary to increase their disease-free and overall survival. Background: MLN8237 is a reversible inhibitor of the Aurora A serine/threonine kinase that showed excellent activity against several tumor types in the Pediatric Preclinical Testing Program. SAHA is a pan-histone deacetylase (HDAC) inhibitor that has shown pre-clinical activity in leukemia, lymphoma, neuroblastoma, and medulloblastoma. HDAC inhibitors decrease Aurora kinases by a variety of mechanisms, and HDAC inhibitors and Aurora kinase inhibitors disrupt the spindle assembly checkpoint at different points, suggesting that the combination could have increased antitumor activity. Methods: We investigated the combination of MLN8237 and SAHA in pediatric cancer cell lines, Molt-4 (pediatric T-cell ALL), IMR32 (neuroblastoma), and Daoy (medulloblastoma). Cell viability was measured using a modified methyl tetrazolium assay after 72 hours of drug treatment, and the cytotoxicity of the drug combination was analyzed using the universal response surface approach as implemented in ADAPT II modeling. For each single drug experiment, two replicate plates were tested, and for the combination drug experiments, four replicate plates were tested. Results: Our results showed that the single agent IC50 for MLN8237 is 0.02 – 0.04 μM in all cell lines. For SAHA, the single agent IC50 ranged from 0.5 μM for Molt-4 to 2.7 μM for Daoy. Both SAHA and MLN8237 inhibited cell survival in a concentration-dependent fashion. Treatment with SAHA resulted in nearly complete inhibition of cell growth in Molt-4 and IMR32 cells at concentrations &gt; 1 μM and 80% inhibition of Daoy cell growth at the maximum concentration of 10 μM, which is well above the clinically relevant concentration range. Maximum inhibition of cell growth in all three lines occurred with 0.05-0.5 μM MLN8237. At concentrations of MLN8237 exceeding approximately 1 μM, there was a paradoxical increase in viability signal in all three lines, most pronounced for Daoy. This may be explained by inhibition of Aurora B kinase which occurs at higher MLN8237 concentrations. Aurora B inhibition leads to metabolically active multinucleated cells. The combination of MLN8237 plus SAHA showed additive cytotoxicity in all three cell lines and nearly abrogated the survival noted at high single-agent MLN8237 concentrations. Conclusion: These results provide important preclinical support for the development of future clinical studies of MLN8237and SAHA.
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 5359. doi:10.1158/1538-7445.AM2011-5359
Abstract 5371: A pooled apoptome shRNA screen to identify pathways that enhance NVP-BEZ235-induced apoptosis
Authors: Buchdunger Elisabeth , Theuer Andreas , Kazic Malika , Hattenberger Marc , Guthy Daniel , Roesel Johannes , Brachmann Saskia , Maira Sauveur-Michel 
Published: June 2012

Abstract
NVP-BEZ235 is a dual inhibitor of class 1 phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) catalytic activity. It induces cell death in a subset of breast cancer cell lines characterized by amplification of human epidermal growth factor receptor 2 (HER2/ErbB2) and/or activating PIK3CA mutations, but not in cell lines with loss of function of the PTEN tumor suppressor protein or KRAS mutations. In order to better understand the molecular mechanisms leading to cell death, to identify potential biomarkers of activity and to reveal pathways that may even enhance NVP-BEZ235 induced lethality, a pooled short hairpin RNA (shRNA) screen using a lentiviral-based shRNA library targeting the apoptome was performed in NVP-BEZ235-sensitive MDA-MB453 and HCC1954 breast cancer cells. This strategy led to the identification of shRNAs that sensitized cells to NVP-BEZ235-induced apoptosis. Top sensitizers included pro-survival BCL2 family members, BCL2L1 and MCL1. Validation studies were carried out with single shRNAs targeting BCL2L1 and MCL1 as well as drug combination studies of NVP-BEZ235 with ABT-263 or ABT-747, both BCL2 homology domain 3 (BH3)-only protein mimetics. Cell death assays and biochemical readouts including PARP cleavage support the use of BCL2 family inhibitors to enhance NVP-BEZ235-induced cell death in HER2 amplified/PIK3CA mutated breast cancer 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 5371. doi:10.1158/1538-7445.AM2011-5371
Abstract 5382: Anti-tumor efficacy of a recombinant human arginase in combination with chemotherapeutic agents in human hepatocellular carcinoma
Authors: Chow Ariel , Pang Roberta , Chu Andrew , Ng Lui , Poon Ronnie 
Published: June 2012

Abstract
Introduction: Systemic chemotherapy of hepatocellular carcinoma (HCC) relies on few drugs and the response rates are low especially in patients with advanced HCC. HCC is considered as auxotrophic for arginine due to the lack of expression of argininosuccinate synthetase (ASS). Several recombinant human arginases were found to be effective in inhibiting liver, pancreatic and leukemic cell proliferation. Recently, a new recombinant human arginase, BCT-100, has been synthesized to deprive arginine and inhibit arginine-dependent tumor growth. In this study, the efficacy of BCT-100 and the combined used of BCT-100 with cisplatin and fluorouracil on the inhibition of in vitro cell proliferation of HCC cell lines and in vivo tumor growth was studied.
Method: The anti-tumor efficacy of BCT-100, cisplatin and fluorouracil, alone or in combination, on cell proliferation, cell cycle distribution and cellular apoptosis were determined in human hepatoma HepG2, Hep3B and PLC/PRF/5 cells. Protein phosphorylation and expression in the Wnt/β-catenin pathways, and expression of cyclin D1, eIF4E, survivin and XIAP, were also analyzed by western blotting. For in vivo animal studies, subcutaneous tumors were established by subcutaneous injections of 1×106 cells into nude mice. BCT-100 in combination with cisplatin or fluorouracil was administrated. Mice were sacrificed week 16 or when tumor sizes exceeded 30% of their body weight.
Results: Treatment with BCT-100 alone was found to inhibit cell proliferation and enhance cellular apoptosis. Additive effect of BCT-100 with cisplatin or fluorouracil was found in inhibiting cell proliferation and increasing apoptosis of HepG2, Hep3B and PLC/PRF/5 cells. Cell cycle arrest at G1/S phase was also observed with BCT-100 treatment. A significant reduction in β-catenin, cyclin D1, phosphorylated eIF4E, survivin and XIAP expression was observed. Furthermore, repeated sequential use of BCT-100 and chemotherapy with either cisplatin or fluorouracil demonstrated synergistic effect of inhibition of tumor growth compared with BCT-100 or chemotherapy alone.
Conclusion: These pre-clinical data suggested additive/synergistic effect of BCT-100 with other chemotherapeutic agents in HCC, which suggested the rationale of combining BCT-100 and chemotherapy in clinical treatment of HCC.
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 5382. doi:10.1158/1538-7445.AM2011-5382
Abstract 5393: Prodrug activator gene therapy mediated by prostate-specific replicating retrovirus vectors
Authors: Kamijima Shuichi , Kimura Takahiro , Haga Kazunori , Hiraoka Kei , Inagaki Akihito , Logg Christopher R. , Kao Chinghai , Bochner Bernard H. , Ichikawa Tomohiko , Kasahara Noriyuki 
Published: June 2012

Abstract
Replicating murine leukemia virus (RMLV)-based vectors can propagate specifically within actively dividing cancer cells and achieve highly efficient and tumor-selective gene delivery. However, in view of the known potential for retroviral integration-mediated genotoxicity, additional mechanisms to target the virus specifically to cancer cells are desirable.
To further improve their tumor specificity and safety profile, we have developed RMLV vectors regulated by two different tissue-specific promoters.
We generated GFP-expressing RMLV vectors ACE-emd (wild type), ACE-At-emd (regulated by ARR2PB promoter, a synthetic variant of the probasin promoter which exhibits high specificity for androgen receptor (AR)-positive prostate cancer cells) and ACE-PSES-emd (regulated by PSES promoter, an androgen-independent promoter which is highly active in PSA/PSMA-positive prostate cancer cells, both in the presence and absence of androgen). We also developed ACE-yCD, ACE-At-yCD and ACE-PSES-yCD carrying the yeast cytosine deaminase (yCD) prodrug-activator gene, which converts the nontoxic prodrug 5-fluorocytosine (5FC) into the chemotoxin 5-fluorouracil.
These vectors were first in vitro tested in both prostate (LNCaP, MDA PCa 2b and PC-3) and non-prostate (293T) cell lines in the presence and absence of androgen. RMLV vector ACE-At-emd exhibited high specificity and robust replication in AR-positive prostate cancer cell lines, but only in the presence of androgen. RMLV vector ACE-PSES-emd exhibited high specificity for PSA/PSMA-positive prostate cancer cell line both in the presence and absence of androgen.
For in vivo studies, male nude mice were inoculated subcutaneously with LNCaP cells (AR-positive, PSA/PSMA-positive) in Matrigel. RMLV vectors expressing GFP were injected intratumorally, and tumors were analyzed by flow cytometry 2 and 4 weeks after vector injection. The results showed that both ARR2PB- and PSES-regulated RMLV vectors achieve efficient gene delivery to LNCaP s.c. tumors in vivo.
Cytotoxic activity of RMLV-yCD vectors was examined in vitro in LNCaP cells in the presence and absence of 5FC after virus infection. Cell-specific expression of each vector correlated with reduced cell viability compared to uninfected cells after 5FC treatment. We are now conducting studies to evaluate therapeutic efficacy vs. potential genotoxicity of these vectors for prodrug-activator gene therapy in vivo.
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 5393. doi:10.1158/1538-7445.AM2011-5393
Abstract 5408: PEG surface modification of Poly(D/L Asp-DET)/DNA polyplexes greatly increases tumor accumulation and improves biodistribution
Authors: Mirosevich Janni , Cardoen Gregoire , Burke Brian , Costich Tara , Sill Kevin 
Published: June 2012

Abstract
Cationic polymers have received much attention as promising non-viral vectors for gene transfer. However, generating polymers that are stable and can systemically deliver large amounts of nucleic acids to specific disease sites continues to be a significant hurdle to non-viral vector success. Therefore, the purpose of this study was to develop a new biocompatible and biodegradable cationic polymer system for non-viral gene delivery of plasmid DNA. Poly-d/l Aspartate-Diethylenetriamine [Poly(d/l Asp-DET)] polymers were synthesized and used to complex plasmid DNA. Polymer/DNA polyplexes were further modified by covalent coupling with various polyethylene glycol (PEG) polymers. Polyplexes were characterized and evaluated for particle size, zeta potential and morphology by TEM. Plasmid DNA stability was assessed by challenging polyplexes with serum nucleases, and the efficacy of DNA delivery and gene expression was examined by performing transfection experiments on cancer cells. In vivo DNA tumor delivery and biodistribution was also investigated using tumor bearing nude mice. Poly(d/l Asp-DET) polymers were able to bind to plasmid DNA and formed polyplex particles the were amenable to surface coating with PEG. PEG-Polyplexes were approximately ∼70nm in diameter with neutral zeta potentials. TEM confirmed that the polyplexes were uniform in size. PEG-Polyplexes were also extremely stable and maintained the structural integrity of DNA following incubation in nucleases, and were also capable of transfecting HCT-116 and PC-3 culture cells with no cell toxicity. Tail vein administration of PEG-Polyplexes to tumor bearing nude mice did not reveal any observable toxicities. Moreover, improvements in PEG polymer chemistry increased nucleic acid accumulation in tumors while reducing DNA accumulation in other tissues including liver, kidney and spleen. Poly(d/l Asp-DET) cationic polymers show enormous potential as non-viral drug delivery agents. Further, the surface modification of polyplexes with PEG allowed for sustained systemic delivery of nucleic acids to tumors. The characterization of PEG-Poly(Asp-DET)/DNA polyplexes provides useful insights that can be used to the design vectors for targeted nucleic acid delivery.
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 5408. doi:10.1158/1538-7445.AM2011-5408
Abstract 5410: Down regulating heavy chain ferritin gene increasesthe radiation therapeutic efficacy for treatment of glioma
Authors: Liu Xiaoli , Madhankumar A.B. , Sheehan Jonas , Slagle-Webb Becky , Connor James R. 
Published: June 2012

Abstract
Gliomas, especially glioblastoma multiforme are resistant to radiation and chemotherapy. Therefore, efforts to develop new course of therapy to enhance efficacy of treatment strategies are obviously critical. We hypothesized that disrupting iron homeostasis in malignant tumor cells could prove effective at negatively affecting tumor growth because cancer cells have a robust iron requirement consistent with their rapid growth and high metabolic rates. The high levels of iron uptake require a mechanism to limit iron induced oxidative damage. This function is the responsibility of ferritin; an iron storage protein with 24 subunits of two types of chains light and heave chains. Heavy chain ferritin (H-ferritin) has been found in the nucleus of tumor cells where it appears to protect DNA from oxidative damage and promote transcription. We hypothesized that silencing the H-ferritin gene could increase the sensitivity of tumors cells to radiation. On the other hand, our previous data already demonstrated that silencing the H-ferritin gene increased chemotherapeutic efficacy for treating gliomas. To test our present hypothesis, the H-ferritin gene will be silenced via a cationic liposome carrying siRNA. We have chosen glioma cell lines (U251, U87 and MNSF) as our in vitro model. Subcutaneous glioma tumor in mouse model (athymic nude mice) was chosen as our in vivo model. Our preliminary in vitro data demonstrated silencing the H-ferritin gene in U251 cells leads to a 50% increase in cell death at 20 Gy for 24, 48 and 72 hours post radiation. Intratumoral injections of cationic liposomes containing H-ferritin siRNA reduced the effective in vivo dose of radiation for tumor suppression by more than 90% at 7 weeks. A supercoil relaxation assay demonstrated that H-ferritin, but not L-ferritin directly protects DNA from radiation by maintaining DNA in a relaxed from. We will further test our hypothesis in glioma-U87, neurofibroma-sNF96.2 and breast cancer-MCF-7 cells. As of now our data shows that silencing the H-ferritin gene appears to be an effective way to increase the sensitivity of the glioma tumors to radiation, which sheds light on increasing the radiation therapeutic efficacy for treatment of malignant tumors.
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 5410. doi:10.1158/1538-7445.AM2011-5410
Abstract 5423: New diazonamide analogs demonstrate remarkably larger therapeutic window compared to taxanes and vinca alkaloids in rodents
Authors: Li Lin , Qi Wei , Zhou Ming , Xu Xiaoming , Harran Patrick G. , Wang Xiaodong , Wang Lai 
Published: June 2012

Abstract
Diazonamide A is a natural product originally isolated from a marine organism. It potently induces G2/M cell cycle arrest. Its molecular mode of action is not fully understood but its potential as a cancer therapeutic is high. To streamline our diazonamide synthesis and to define a minimal pharmacophore, we prepared a series of truncated structures. Its simplified structure and shortened synthesis allowed for extensive structure activity relationship analyses. Several modifications markedly improved activity. Among them, JP2295 and JP2362 were studied in details. Both compounds were highly efficacious in a wide spectrum of tumors from different origin both in vitro and in vivo. They were &gt;20 fold more potent than AB5, a closely related analog of the natural product, in a MIA Paca-2 pancreatic cancer xenograft model. At dose 10-fold higher than the efficacious dose, JP2295 or JP2362 did not cause any apparent toxicity. Three out of 7 mice were completely free of tumor even 6 months after the initial treatment. In the same model, taxanes, i.e. paclitaxel and docetaxel, and vinca alkaloids, i.e. vinorelbine, vinblastine, and vincristine, were either less efficacious or causing severe body-weight loss, even animal death. Similar effects were observed in other xenograft models. Safety studies were further carried out in NIH Swiss mice and Sprague Dawley rats with similar results. In summary, JP2295 and JP2362 demonstrated over 20-fold bigger therapeutic window than taxanes and vinca alkaloids in rodents. Such a large therapeutic window is unique for a small molecule anti-mitotic and suggests further development is warranted.
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 5423. doi:10.1158/1538-7445.AM2011-5423