bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5533: Anti-proliferative and anti-tumor effects of a novel vitamin D derivative, either alone or in a liposomal formulation in malignancies of kidney, pancreas and prostate
Authors: Ray Rahul , Lambert James R. , Persons Kelly S. , Eddy Vikram J. 
Published: February 2011

Abstract
1,25-dihydroxyvitamin D3 (1,25(OH)2D3) has well-known potential in cancer-therapy; but such a potential is marred by its severe toxicity in pharmacological doses. 1α,25-dihydroxyvitamin D3-3-bromoacetate (1,25(OH)2D3-3-BE) is a novel derivative of 1,25(OH)2D3 which enables covalent attachment of 1,25(OH)2D3 inside the ligand-binding pocket of nuclear vitamin D receptor, thus increasing the half-life of 1,25(OH)2D3 and potentially reducing its therapeutic dose with less toxicity. We have observed that 1,25(OH)2D3-3-BE strongly hinders the growth of cells representing malignancies of prostate (androgen-sensitive and androgen-insensitive), pancreas and kidney. However, growth of normal kidney and prostate cells is not affected by this compound. Inhibition of cell-growth by 1,25(OH)2D3-3-BE involves hindrance to cell-cycling, and enhancement of apoptosis and autophagy; and includes several mechanisms involving VDR-mediated nuclear pathway and inhibition of Akt-phophorylation. We have also observed that 1,25(OH)2D3-3-BE strongly inhibits the growth of prostate and renal tumors in mouse xenograft models. In anticipation of its therapeutic potential we prepared a liposomal formulation of 1,25(OH)2D3-3-BE to enhance its efficacy further by potentially preventing its premature degradation and tumor-targeting. We report that liposomal 1,25(OH)2D3-3-BE is a significantly stronger growth-inhibiting compound than naked 1,25(OH)2D3-3-BE in prostate, kidney and pancreatic cancer cells. This property is also manifested in a mouse xenograft model of androgen-insensitive prostate tumor. In summary, 1,25(OH)2D3-3-BE and its liposomal formulation demonstrate a strong translational therapeutic potential in cancers of kidney, pancreas and prostate.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
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 5533.
Abstract 5534: Liposome accumulation within leukemia engrafted bone marrow is significantly enhanced when the formulation contains cytarabine plus daunorubicin
Authors: Johnstone Sharon A. , Xie Sherwin , Harasym Troy , Mayer Lawrence , Tardi Paul G. 
Published: February 2011

Abstract
CPX-351 is a liposome formulation designed to deliver a synergistic, fixed ratio of cytarabine and daunorubicin in vivo. It has been shown to be highly efficacious against a variety of mouse leukemia models and encouraging evidence of anti-leukemic activity has been observed in clinical trials. In this report we investigate liposome biodistribution properties that may contribute to the enhanced efficacy of CPX-351. In order to model bone marrow leukemia development, we utilized the human leukemia CCRF-CEM tumor which has been shown to efficiently engraft to the bone marrow of SCID Rag2M mice. Liposomes were prepared in the presence or absence of cytarabine and daunorubicin to compare the plasma clearance and biodistribution to bone marrow, liver, lung, spleen and kidney following multiple treatments. The plasma clearance of empty liposomes and CPX-351 were similar in both leukemia and non-leukemia bearing mice. Both liposomal formulations had similar organ distribution profiles in the presence or absence of leukemia; however lipid delivery to the bone marrow was markedly augmented by the presence of encapsulated drug. Accumulation of CPX-351 lipid in the bone marrow was 20 to 50% higher than for empty liposomes and this phenomenon was further enhanced in leukemia bearing mice. Leukemia-laden bone marrow accumulated 75% more CPX-351 lipid than the empty liposomes on the first injection and accumulation increased an additional 20% with subsequent injections. We attribute the increased efficacy of CPX-351 over the free drug cocktail of cytarabine and daunorubicin to elevated exposure of the tumor tissue to chemotherapeutic agents. This increased exposure is not only due to the prolonged circulation of the drug in the liposomes, but also due to the increased bone marrow uptake of the liposomes when drugs are present. Additionally the lipid accumulation is further increased with successive treatments of the leukemia. The results suggest that the liposomal drugs alter either the bone marrow microenvironment or resident cell populations in a manner that facilitates subsequent uptake and/or retention of CPX-351.
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 5534.
Abstract 5539: Analysis of antitumor activity of IL-13PE in combination with gemcitabine for human pancreatic ductal adenocarcinoma therapy
Authors: Fujisawa Toshio , Nakashima Hideyuki , Nakajima Atsushi , Joshi Bharat H. , Puri Raj K. 
Published: February 2011

Abstract
Previously, we have identified an overexpression of IL-13Rα2 in 71% of human pancreatic ductal adenocarcinoma (PDA) specimens. We have also demonstrated that these receptors can be a target for a receptor directed chimeric cytotoxin, IL-13PE, which consists of IL-13 and a truncated Pseudomonas exotoxin (IL13-PE). In the present study, we examined the anti-tumor activities of IL13-PE in combination with gemcitabine, an established first line therapy for advanced pancreatic cancer. Both these agents were cytotoxic to two pancreatic cancer cell lines (HS766T and MIA-PaCa2) with IC50 of 1.1 - 51 ng/ml and 19 - 98 nmol/L, respectively. Upon combination of these two agents, we observed a synergistic cytotoxicity in these two cell lines (IC50: 0.4 ng/ml with 0.01 nmol/L gemcitabine in HS766T and 21 ng/ml with 1 nmol/L gemcitabine in MIA-PaCa2). In addition, we have demonstrated a synergistic anti-tumor activity in an orthotopic mouse model of human PDA developed in athymic nude mice. This study showed complete eradiation of tumors as assessed by whole body imaging of GFP-transfected tumors in 57% of mice in an early cancer model and also resulted in a prolongation in survival. In contrast, single therapy with either IL13-PE or gemcitabine did not produce complete eradiation, but tumor volumes were significantly decreased. In advanced cancer models, IL13-PE and gemcitabine also produced a dramatic reduction and retardation of tumor growth and enhanced survival compared to animals treated with either agent alone. Furthermore, silencing of IL-13Rα2 by RNAi in tumor cells prior to tumor implantation revealed that the combination of IL13-PE and gemcitabine was less effective in this model indicating that IL-13Rα2 is an essential target in PDA for complete elimination of tumors. Mechanistically, gemcitabine increased IL-13Rα2 mRNA expression in vitro and in vivo, which in turn, resulted in a synergism of combination therapy and improved induction of apoptosis in PDA cell lines. Based on these data, we conclude that combination therapy of IL13-PE and gemcitabine may be an additional therapeutic option for management of pancreatic ductal cancer patients for better clinical outcome.
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 5539.
Abstract 5540: Targeting type 1 insulin-like growth factor receptor enhances radiosensitivity in human liposarcoma cell lines
Authors: Kuang Jonathan , Knittel Tony Z. , Goldstein David , Yang Jia Lin 
Published: February 2011

Abstract
Soft tissue sarcoma (STS) is currently treated by surgery and adjuvant or neoadjuvant radiotherapy. About 20 - 30% of patients develop local recurrence and 50% will eventually die of their disease. Adjuvant cytotoxic therapies improve disease free survival but overall survival is minimally effected. New treatments are required. As with many cancers there is an imbalance between cell growth and cell death and this also the case with STS. Cell growth signals such as those from the insulin-like growth factor receptor (IGF-1R) increases resistance to radiotherapy. We proved that IGF-1R family members are highly expressed in sarcoma tissue samples, particularly IGF-1R 80% positive, which is also significantly associated with histologic grade. This study investigates whether inhibiting IGF-1R can improve the sensitivity of radiotherapy in liposarcomas.
Expression of IGF-1R and/or activated IGF-1R in 3 liposarcoma cell lines was detected by western blot and immunoprecipitation respectively. Crystal violet staining and/or clonogenic assays were used to assess anti-proliferative effects of irradiation and IGF-1R inhibitor (tyrphostin AG1024) or IGF-1R downstream pathway inhibitors (LY294002 and SB202190). Irradiation was performed using Therapax DXT300 Orthovoltage Radiation System.
We found that the IGF-1R inhibitor can enhance radiotherapy, particularly in the 2 radio-insensitive sarcoma cell lines (combination index &lt;1 = synergism, CI &lt;0.1 for 449B; CI 0.1-0.3 for 778). The drug reduction index (DRI) at IC50 measures how much the dose of x-ray may be reduced when drug and x-ray were combined at the IC50 effect level compared with the dose of x-ray alone. The DRI for 449B and 778 was 3 and 5 fold for x-ray reduction respectively. In addition, we found that radiation can induce activation of IGF-1R in the sarcoma cell line detected with peak time at 4 hours. Using the IGF-1R inhibitor pre-treatment achieved more inhibitory effect than concurrent inhibitor plus X-ray or X-ray alone group. The greatest enhancement of radiosensitivity was observed with pre-treatment of AG1024 followed by combination therapy, resulting in an 80% decrease in cell survival fraction at the highest dose combination. We also used PI3K and p38 pathway inhibitors singly or together compared with the IGF-1R inhibitor in the presence or absence of X-ray or IGF-1 and discovered that both pathways are involved in radioresistance and the inhibition is at least partially IGF-1R dependent.
Targeting the IGF-1R to radiosensitize liposarcomas is a novel treatment strategy that can potentially improve the prognosis of some patients with low radiosensitive liposarcoma.
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 5540.
Abstract 5546: Improved gastrointestinal repair post irradiation with AEOL 10150
Authors: Booth Catherine , Tudor Gregory , MacVittie Thomas , Day Brian , McManus John 
Published: February 2011

Abstract
Background
Gastrointestinal toxicity, often manifested as ulceration and diarrhoea (mucositis) occurs following exposure to radiation and many chemotherapeutics. Potential treatments include prophylactic damage limitation or therapeutic/mitigatory wound repair dosing regimes. Treatments that are effective mitigators also have biodefence applications. In both the clinic or following nuclear terrorism effective agents may be given in combination with haematological therapies, in addition to standard supportive care agents.
Methods
AEOL 10150 [5,10,15,20-tetrakis(1,3-diethylimidazolium-2-yl) porphyrinato] manganese (III) pentachloride was administered to C57BL/6 male mice s.c. daily from 24hrs following a single dose of 13Gy total body X-irradiation. AEOL 10150 was administered at a 2x initial loading dose of 40 or 20mg/kg and then subsequently each day at 20 or 10mg/kg respectively. Animals were euthanized 4 and 6 days post irradiation and the number of regenerating small intestinal crypts measured. In a parallel study the levels diarrhoea and animal viability were measured animals exposed to 15Gy partial body X-irradiation (partially lead shielded to protect the bone marrow).
Results
Treatment with AEOL 10150 increased the number of surviving regenerating crypt observed in histological cross sections of the small intestine 4 days post irradiation. This was highly significant at both doses (p&lt;0.001 for the 40/20mg/kg schedule and p=0.009 for the 20/10 mg/kg schedule). By day 6, where crypt numbers had increased from day 4, numbers were increased but not statistically significant. Levels of crypt fission, necessary to restore crypt numbers, were also increased. At the highest treatment dose animal mortality was only marginally reduced (p=0.115) but the severity and duration of observed diarrhoea was significantly reduced (p=0.021 and p=0.010 respectively).
Conclusion
AEOL 10150 demonstrated efficacy in both histological and physiological readouts of radiation induced gastrointestinal toxicity. Studies are currently ongoing to investigate whether other dosing schedules can further improve gastrointestinal repair.
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 5546.
Abstract 5553: Liposomal rhenium by convection enhanced delivery for primary brain tumors
Authors: Brenner Andrew , Trevino Abram , Rogge Jessica , Goins Beth , Giles Francis , Phillips William 
Published: February 2011

Abstract
Introduction: While adjuvant external beam radiation prolongs survival in glioblastoma, doses must be limited to approximately 60Gy secondary to lack of benefit and increased toxicity with higher doses. Despite maximum radiation, 90% of tumors recur at the original site. Convection enhanced delivery (CED) of radiation has the potential of administering higher doses locally to the tumor while reducing toxicity to normal brain parenchyma. Lipid nanocarriers offer the potential of distribution though the tumor as well as retention within the tumor. We hypothesized that a radionuclide liposome generated with a specially developed chemistry for loading a large quantity of rhenium, delivered by CED, would allow a higher dose of radiation to be delivered safely and effectively.
Methods: Intracranial xenografts were established in nude rats with luciferase expressing U87 glioma cell line. To establish the correct volume of administration, liposomes were labeled with technetium99 and administered intratumorally by CED in volumes of 50 and 100ul at variable rates and imaged by SPECT/CT. Once volume and rate were established, an initial dose range finding study was performed with Re186 doses from 25 to 125uCi. The maximum tolerated dose was then assessed for efficacy as well as to confirm absence of toxicity. Tumor growth was followed by in vivo bioluminescent imaging and 7T MRI. Rats were sacrificed when moribund or when marked neurologic deficit was observed. Rat brains were evaluated by standard histologic methods for residual tumor, gliosis and necrosis.
Results: Technetium liposomes in smaller volumes appeared to have better local retention with up to 60% retained at 22 hours post injection. Rats bearing U87 tumors treated with liposomal Rhenium186 tolerated the maximum administered dose of 125uCi (∼550Gy) without apparent toxicity, evidence of necrosis or gliosis. Efficacy was confirmed with rats treated at maximum dose, with all rats in the maximum dose continuing to survive and gain weight to 70 days post tumor inoculation, as compared to control rats which expired between 38 and 44 days.
Conclusions: High doses (approx 550Gy) can be delivered to intracranial tumors in tumor bearing rats by CED of rhenium nanoliposomes. No evidence of neurotoxicity or histological changes suggestive of normal tissue injury are observed despite these very high doses. Rhenium liposomes delivered by CED show significant antiglioma activity with prolonged survival of treated tumor bearing rats. Further experiments are warranted to evaluate the potential of Rhenium 186 liposome in the treatment of glioblastoma and other primary brain tumors.
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 5553.
Abstract 5555: Quantitative Proteomic Profiling of Matched Normal and Tumor Breast Tissues
Authors: Sutton Chris , Rustogi Nitin , Scally Andrew , Gurkan Cemal , Loizidou Maria , Hadjisavvas Andreas , Kyriacou Kyriacos 
Published: February 2011

Abstract
Introduction - Quantitative proteomic profiling of breast tissue has proven difficult due to its inherent histological complexity. Substantial differences in stroma, vasculature and cellular composition of normal and tumors have further exacerbated analysis. In order to address these issues, a novel strategy for proteomics analysis was developed to determine differences between normal and disease tissue and between patients with adenoma and invasive carcinoma.
Methods - A dual lysis buffer method for extracting proteins, in combination with sonication, was used to maximise recovery from normal and diseased breast biopsies. Protein extracts from matched normal breast and tumors of three patients (one with adenoma and two with invasive carcinoma) were trypsin-digested, were iTRAQ (isobaric tag for relative and absolute quantitation) labelled, pooled and the resulting peptide mixture separated using isoelectricfocusing in the first dimension and reverse phase nanoHPLC in the second dimension. The eluate from nanoHPLC was collected onto matrix assisted laser desorption/ionisation plates, analysed by MALDI MS and MS/MS, the subsequent data searched against a sequence database to identify proteins in the original sample.
Results - A total of 481 proteins with associated normal: tumor iTRAQ ratios for each patient. iTRAQ ratios were indicative of increased or decreased levels of each protein in tumor compared to normal tissue. Proteins were categorised by location as blood (13% of the identified proteins), extracellular (12%) and cellular (75%). The average ratios for each group of proteins provided a gross indication of the relative levels of each tissue component in the matched normal and tumor biopsies and demonstrated marked difference in adenoma compared to invasive carcinoma. iTRAQ ratios were normalised to enable comparison of significantly changed proteins between patients. There were many cellular proteins in common between the two invasive carcinoma patients (54 increased and 51 decreased in tumors) but few between either of the invasive carcinoma patients and the adenoma patient.
Discussion - A number of proteins significantly increased or decreased have previously been associated with breast cancer (Tropomyosin beta chain, Periostin, Small breast epithelial mucin and Breast cancer estrogen-inducible protein were increased and Selenium-binding protein 1, Secreted frizzled-related protein 1 precursor and Kinectin were decreased), supporting the approach we have developed for proteomics analysis of breast tissues.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
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 5555.
Abstract 556: Extracellular matrix protein mixture isolated from cultures of human tumor and stromal cells supports growth of human tumor cells in vitro and in vivo
Authors: Mishra Pravin J. , Mishra Prasun J. , Gao Hui , Glod John , Banerjee Debabrata 
Published: February 2011

Abstract
Carcinoma Associated Fibroblasts (CAFs) along with other cells present in the tumor milieu play a major role in tumor progression. We have previously demonstrated differentiation of human bone marrow derived mesenchymal stem cells to CAF like phenotype upon exposure to tumor conditioned medium. The present study evaluates the ability of these stromal components to support tumor progression. An in vitro system was used to study impact of the components of the tumor milieu on growth of luciferase expressing MDA MB 231 cells, representing basal subtype of human breast cancer. CAFs along with phorbol ester induced HL60 cells representing a macrophage like phenotype supported growth of MDAMB231 cells in vitro as measured by a luciferase assay. When injected subcutaneously in vivo in nu/nu mice, tumor cells comingled with CAFs or with differentiated HL60 cells showed almost similar tumor growth rate, whereas CAFs and differentiated HL60s when mixed together showed more than 4 fold increased tumor growth rate compared to the tumor cells alone and 2 fold compared to tumor cells plus MatrigelTM.
Electrophoretic analysis of extracellular matrix protein mixture isolated from mixed cultures of CAFs plus MDAMB231 cells and differentiated HL60 cells (3 cells) using previously published methods showed presence of laminins and collagens, and demonstrated robust tumor cell growth compared to MatrigelTM. The ECM protein mixture derived from the three cell system offers a completely humanized substitute for MatrigelTM useful for study of tumor growth and response to therapy in vitro as well as in vivo.
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 556.