bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5521: IL13 linked lipsomal doxorubicin for malignant peripheral nerve sheath tumors
Authors: Madhankumar Achuthamangalam B. , Slagle-Webb Becky , Park Annie , Klinger Marianne , Pang Min , Harbaugh Kimberly , Sheehan Jonas M. , Connor James R. 
Published: February 2011

Abstract
We have previously demonstrated the therapeutic effect of interleukin-13 (IL13) linked liposomal doxorubicin (IL13LDXR) on glioma tumors. These tumors selectively overexpress IL13 receptor α2, a receptor for IL13. In our subsequent study, we found that malignant peripheral nerve sheath tumors (MPNST) also express the receptor for IL13. This observation prompted us to investigate the therapeutic value of IL13LDXR in a MPNST model. IL13LDXR was formulated and characterized in our laboratory using our previously established method. In vitro binding and internalization studies and subsequent fluorescence microscopy demonstrated the effective nuclear delivery of the doxorubicin in the MPNST cells expressing IL13Rα2 receptor. The cytotoxic potential of IL13LDXR was demonstrated in MPNST cell lines sNF96.2, ST88-14 and #215. Immunohistochemistry was performed on malignant and benign peripheral nerve sheath tumor (PNST) sections ex vivo to determine the expression of IL13Rα2 receptor. In addition we also demonstrated the expression of P-glycoprotein, a multidrug resistant protein in MPNST cell lines by immunocytochemistry. We also studied the effect of IL-13 protein in altering the expression of Pgp expression in established MPNST cell lines. We confirmed by an immunoblot that IL13 protein at 5µM concentration was able to decrease the Pgp expression in ST88-14 and sNF96.2 cells. This may explain the mechanism by which the IL-13 conjugated liposomes can deliver the encapsulated doxorubicin in a much more effective manner to drug resistant MPNST cell lines. We investigated the correlation of IL13Rα2 receptor expression with P-glycoprotein a drug resistance associated protein by immunocytochemistry. We confirmed the expression of IL13Rα2 in PNST tumors and established MPNST cell lines. We attempted to develop a MPNST tumor model in athymic nude mice by matrigel implantation method. We administered a single injection of 15 mg/kg of IL13 linked liposomal doxorubicin in a mouse tumor model by intraperitoneal route and observed the selective accumulation of doxorubicin in the tumor by endogenous fluorescence of doxorubicin, whereas no fluorescence was observed in the normal skin region as observed under fluorescence microscope. In conclusion consistent expression of IL13Ra2 receptors in PNST and MPNST cells and tissues indicate a viable approach to use this receptor as a target for MPNST therapy. The doxorubicin accumulation property and its cytotoxic potential on MPNST cells when delivered though the targeted liposomes envisage IL13LDXR as a potential drug for MPNST.
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 5521.
Abstract 5523: Gold nanoshells in the treatment of high-grade gliomas in a mouse model
Authors: Thompson Patrick A. , Day Emily S. , Zhang Linna , Wong Kelvin , Gaber Mostafa W. , Blaney Susan M. , West Jennifer L. 
Published: February 2011

Abstract
Purpose: To evaluate the anti-tumor activity of near-infrared (NIR) absorbing gold-silica nanoshells against high grade gliomas in an in vivo subcutaneous mouse model. Background: Nanoshells with a silica core and a gold outer layer, which are optically tunable with peak absorption between 790 and 810 nm, have been shown to preferentially accumulate in colon cancer models after i.v. administration as a result of the enhanced vascular permeability and retention effect. When the tumor is illuminated with NIR light, the gold nanoshells are thermally activated. This results in tumor ablation without damage to normal tissues, since NIR light is not appreciably absorbed by tissue components at these wavelengths. High-grade gliomas are an attractive target for this type of therapy because the vast majority of tumors remain incurable with multi-modality therapeutic approaches, with local control being the primary manifestation of disease progression or recurrence. Methods: Gold silica nanoshells were synthesized according to previously published procedures. Survival studies were performed in NOD SCID mice with subcutaneous U373 glioma tumors in the right hind flank. When the tumor diameter was 3-5 mm, either 100 µl of PEG-coated nanoshells (treatment group, n =7) or 100 µl of saline (control group, n=8) were injected via tail vein. Twenty-four hours later tumors were exposed to an 808 nm diode laser at 4 W/cm2 for 3 minutes. Mice were monitored daily following treatment and euthanized when tumors reached 10 mm in largest diameter. Results: In the subcutaneous xenografts the overall survival at 90 days was 57% in the treatment group and 0% in the control group. None of the control group mice survived past 24 days. In addition, all of the mice in the treatment group that were still alive at 90 days were completely tumor-free without any sign of recurrence. Conclusions: These studies demonstrate that gold nanoshells can accumulate in subcutaneous glial tumors at levels sufficient to improve survival following thermal activation with NIR light.
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 5523.
Abstract 5527: Short-chain glucosylceramide improves doxorubicin delivery in spontaneous mouse breast carcinomas
Authors: van Hell Albert J. , van Lummel Menno , Koning Gerben A. , van Blitterswijk Wim J. , Verheij Marcel 
Published: February 2011

Abstract
Background: Insufficient delivery of chemotherapeutic agents to their intended intracellular targets within the tumor remains a major obstacle in clinical oncology. Most of these drugs are amphiphilic and their diffusion through the plasma membrane is, therefore, slow and a major limitation for sufficient uptake within the tumor cell. We have found that certain short-chain sphingolipids enhance the intratumoral drug accumulation by modulation of inward translocation of cytostatics over the plasma membrane. Here, we examine this novel approach in an in vivo mouse model of aggressive invasive lobular breast carcinoma (ILC), designed to closely mimic its human counterpart.
Results: In a panel of cell lines, short-chain sphingolipids, such as C8-glucosylceramide (GC) increase the intracellular accumulation of doxorubicin up to 4-fold. A clinically approved drug carrier (100 nm liposomes) was employed for co-delivery of both lipid and drug to the tumor tissue. The addition of 10 mol% GC markedly enhanced the cellular doxorubicin content in vivo, as was demonstrated with intravital fluorescence microscopy. In the metastatic and aggressive mouse ILC tumors, the efficacy of GC doxorubicin liposomes was significantly improved compared to the currently applied conventional doxorubicin liposomes. The enrichment with the GC membrane modulator resulted in a significant tumor growth delay (p = 0.0119) and an overall survival benefit (p = 0.0143) for mice treated with the GC enriched liposomal doxorubicin as compared to conventional liposomes.
Conclusion: Short-chain sphingolipids improve the translocation of various cytostatics, including doxorubicin, over the plasma membrane of tumor cells. This membrane modulating strategy can be successfully applied in vivo, e.g. as a co-formulation with doxorubicin liposomes, thereby enhancing their anti-tumor efficacy. Furthermore, our data suggest that GC-enriched doxorubicin liposomes hold promise as anti-neoplastic therapy in human breast cancer.
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 5527.
Abstract 5528: Toxicology and drug delivery by Cucurbit[n]urils and derivatives
Authors: Hettiarachchi Gaya , Nguyen Duc , Wu Jing , Lucas Derick , Ma Da , Isaacs Lyle , Briken Volker 
Published: February 2011

Abstract
Drug candidates are continuously being discovered using high-through put screens of small compound chemical libraries, however, many of these drugs are not pursued into development because of low bioavailability. Therefore, drug delivery systems that improve bioavailability are of great importance. Cucurbit[n]urils (CB[n]) are a new class of molecular container compounds that are beginning to show great promise as a novel drug delivery system. Here we analyzed the toxicology of two unmodified cucurbit[n]urils, (CB[5] and CB[7]), and three CB[n] derivatives (Pentamer, Me-Hexamer and Ph-Hexamer). All five containers showed high cell tolerance at concentrations of up to 1mM in HEK293, HepG2 and RAW264.7 cell lines using assays for metabolic activity and cytotoxicity. We also studied uptake, and bioactivity using CB[7], the most soluble of the containers presented above. Bioactivity assays conducted with RAW264.7 cells infected with M. Smegmatis showed no inhibition of the activity of the antituberculosis drug ethambutol (EMB) by CB[7] after 3 days of incubation. This study provides a proof of principle towards the use of these containers as a novel drug delivery system.
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 5528.
Abstract 5532: Folate receptor expression in human malignancies to select patients who would benefit from folate conjugated therapy
Authors: Covello Kelly L. , Wiebesiek Amy , Alland Leila , She Yijin , Wu Qiuyan , Lee Francis 
Published: February 2011

Abstract
The folate receptor (FR) is expressed on a number of human tumors, including ovarian, renal, lung, and breast. Folic acid is the ligand for the FR and many innovative strategies for targeting therapeutics to tumors make use of this ligand/receptor pair. Novel therapeutic approaches include folate conjugation to cytotoxics or radiopharmaceuticals, folate-coated liposomes containing antisense oligonucleotides, folate conjugates of pro-drugs, and folate-linked nanoparticle carriers for therapeutic drugs and genes. Potential patient enrichment strategies are necessary to allow for better targeting of these agents to those patients who have FR expressing tumors. Preclinical experiments to evaluate the molecular correlation of FR levels by three different methods, qRT-PCR, IHC, and the radiolabeled ligand binding assay, were conducted. A total of seventeen samples (four xenografts and thirteen primary patient ovarian and endometrial tumor biopsies) were evaluated for FR expression in these three independent assays and the FR levels correlated in this sample size. Compared to a preclinical model that was sensitive to epothilone-folate conjugate therapy, most patient samples expressed higher FR levels. These data provide a reliable and useful method to identify patient tumors that express the FR above a baseline determined to be sufficient for response to folate-conjugated therapy in preclinical models.
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 5532.
Abstract 5535: Delivery of siRNA via functionalized lipopolyamine systems
Authors: Polach Kevin J. , Sparks Jeff , Congo Richard , Slobodkin Gregory , Rea-Ramsey Angela , Pence Casey , Matar Majed , McClure Diane , Rice Jennifer , Brunhoeber Elaine , Wilkinson Leslie , Anwer Khursheed , Fewell Jason G. 
Published: February 2011

Abstract
The efficient delivery of siRNA molecules to target cells is critical for the application of RNAi to the treatment of human cancers. To this end, we have developed novel cationic lipopolyamime structures that can be used to complex or encapsulate siRNA into nanoparticles for efficient in vitro or in vivo delivery. Unlike conventional cationic delivery systems, these lipopolyamines are chemically flexible which allow for covalent attachment of functional moieties which can modulate their biological activity. For example, modification of these systems with serum stabilizing agents allows for modulation of physical parameters important for biological properties such as toxicity and biodistribution. Intravenous (iv) injection of these functionalized nanoparticles showed preferential distribution to the lungs and corresponding depletion of targeted mRNA transcripts from lung tissue. We have investigated these systems for use in delivering siRNA targeting VEGF in mice with advanced disseminated ovarian cancer through intraperitoneal (ip) injection of siRNA-lipopolyamine nanoparticles. This model was established by injecting animals (ip) with 2.5×106 ID8 cells (malignant transformed ovarian surface epithelial cells that have been further modified to overexpress VEGF protein). Delivery of serum stabilized complexes to the peritoneal cavity of mice with disseminated ovarian cancer resulted in significant target gene knockdown in cells obtained from the malignant ascites fluid of these animals with modest knockdown in the peritoneal tumors themselves. A further modification of the core lipopolyamine structure incorporated attachment of a targeting peptide ligand through a linker molecule. Physico-chemical characterization of this targeted system and in vitro assays with ID8 cancer cells demonstrated specific delivery of siRNAs dependent on the presence of the targeting ligand on the liposome and the targeted receptor on the cell surface. These results have prompted in vivo testing using the targeted delivery systems to assess siRNA distribution as a function of delivered dose. Additional studies are underway that will establish the optimized delivery conditions for use in tumor bearing animals.
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 5535.
Abstract 554: Crosstalk between TNF-α and IGF signalling increases IL-6 production and protects tumor cells from TNF-α-induced apoptosis in the liver
Authors: Li Shun , Yang Long , Lin Rongtuan , Hiscott John , Brodt Pnina 
Published: February 2011

Abstract
Background: Liver metastasis is a common and often fatal occurrence in cancer patients. A better understanding of the biology of liver metastasis is essential to improve survival statistics for these patients. We have previously shown that metastatic lung and colon carcinoma cells that invade the liver initiate a rapid host inflammatory response that entails increased production of cytokines TNF-α and IL-1 and results in increased tumor adhesion, transmigration and metastasis. TNF-α is a pleiotropic cytokine that can also induce tumor cell apoptosis. We hypothesized that the ability of tumor cells to form liver metastases in the face of increased local TNF-α levels is due to an acquired resistance to the tumoricidal effects of TNF-α. The objective of the present study was therefore to identify molecular mechanism(s) that regulate the tumor cell response and sensitivity to TNF-α.
Methodology: We used a Lewis lung carcinoma-based tumor model consisting of poorly metastatic subline M-27 cells in which ectopic expression of the type 1 insulin-like growth factor receptor (IGF-IR) markedly increased the liver-metastasizing potential of the cells. TNF-α-mediated signalling in these (M-27IGFIR) and wild-type (M-27) cells were analyzed by a combination of Western blotting, electrophoretic mobility shift assays, cytokine profiling, immunofluorescence labelling and flow cytometry.
Results: We found that IGF-I receptor overexpression in the tumor cells altered TNF-α-mediated signalling by accelerating TNF-α-induced IκBα phosphorylation and degradation and enhancing nuclear translocation of NFκB. This resulted in increased IL-6 production in M-27IGFIR, but not M-27 cells in response to TNF-α. IL-6 expression could be further augmented by co-stimulation with IGF-I, an effect that was mediated via PI3-K signalling. Furthermore, the level of activated STAT-3 in M-27IGFIR cells was significantly increased, suggesting that IL-6 could activate STAT-3 in these cells through an autocrine mechanism. Finally, when apoptosis induction by TNF-α in these cells was compared using antibodies to cleaved caspase 3, a significant reduction in the proportion of apoptotic cells was seen in TNF-α-treated M-27IGFIR as compared to M-27 cells.
Conclusions: Taken together, the results suggest that overexpression of IGF-IR altered TNF-α signalling in the tumor cells, shifting the response towards increased IL-6 production and autocrine STAT-3 activation, thereby providing the cells with a survival advantage in the presence of TNF-α.
Supported by Canadian Institute for Health Research grant MOP- 81201 (PB) and a McGill University Health Center Research Institute fellowship (SL).
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 554.
Abstract 5543: Combining antibody-targeted radiation (radioimmunotherapy) and antibody-SN-38 conjugates (ADC) improves pancreatic cancer therapy
Authors: Karacay Habibe , Govindan Serengulam V. , Sharkey Robert M. , Goldenberg David M. 
Published: February 2011

Abstract
We previously reported effective anti-tumor activity in nude mice bearing human pancreatic tumors with 90Y-humanized PAM4 IgG (hPAM4; 90Y-clivatuzumab tetrexetan) that was enhanced when combined with gemcitabine (GEM). These studies led to clinical testing of fractionated 90Y-hPAM4 IgG combined with GEM that is showing encouraging objective responses. While GEM is known for its radiosensitizing ability, alone it is not a very effective therapeutic agent for pancreatic cancer and its dose is limited by hematologic toxicity, which is also limiting for 90Y-hPAM4 IgG. We recently reported promising anti-tumor activity with an ADC composed of hRS7 IgG (humanized anti-epithelial glycoprotein-1; EGP-1) and SN-38, the active component of irinotecan. This ADC is very well tolerated in mice (eg, ≥ 60 mg), yet just 4.0 mg (0.5 mg, twice-weekly x 4) is significantly therapeutic. Since EGP-1 is also expressed in most pancreatic cancers, we have examined combinations of 90Y-hPAM4 IgG with RS7-SN-38 in nude mice bearing 0.35 cm3 subcutaneous xenografts of the human pancreatic cancer cell line, Capan-1. Mice (n=10) were treated with a single dose of 90Y-hPAM4 IgG alone (130 µCi, ie, the maximum tolerated dose or 75 µCi), with RS7-SN-38 alone (as above), or combinations of the 2 agents at the two 90Y-hPAM4 dose levels, with the first ADC injection given the same day as the 90Y-hPAM4. All treatments were tolerated, with ≤ 15% loss in body weight. Objective responses occurred in most animals, but they were more robust in both of the combination groups as compared to each agent given alone. All animals in the 0.13 mCi 90Y-hPAM4 IgG + hRS7-SN-38 achieved a tumor-free state within 4 weeks, while other animals continued to have evidence of persistent disease. These studies provide the first evidence that combined radioimmunotherapy and ADC can enhance efficacy at safe doses. (Supported in part by SBIR grant 2R44CA1148 from the NCI.)
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 5543.
Abstract 5545: Functional antagonism between vorinostat and temozolomide when combined with ionizing radiation (IR) in glioblastoma
Authors: Lawrence Yaacov R. , Liu Yi , Andersen Barbara , Xia Xu , Dicker Adam P. , Wachsberger Phyllis 
Published: February 2011

Abstract
Background: Glioblastoma is the most common primary adult brain tumor. Surgery followed by radiation therapy in combination with temozolomide (Tmz) produces a median survival of 14.6 months. Tmz is a DNA akylating agent that leads to the mispairing of guanine residues with thymine. An intact mismatch-repair mechanism (MMR) converts the mispaired thymine into a lethal double-strand DNA break. Vorinostat (SAHA), an HDAC inhibitor, has been shown to act as a radiosensitizer, possibly through inhibition of DNA repair. SAHA has successfully been combined with a number of cytotoxic agents. We hypothesized that SAHA would further potentiate the radiosensitizing properties of Tmz in glioblastoma.
Materials/Methods: Experiments were performed with 2 glioblastoma cell lines (U87, LN18). DNA double strand breaks were quantified by both neutral comet assay and gamma-H2AX immunohistochemistry. Assays were performed immediately, and 24 hours after IR to assess DNA damage and repair respectively. For the neutral comet assay the dose of radiation was 30 Gy and the ‘olive moment’ was scored. The magnitude of the olive moment correlates with increasing DNA damage. For gamma-H2AX assay, the dose of radiation was 2 Gy and the percentage of cells with more than 3 foci was scored. Quantitative PCR and clonogenic cell survival were performed using standard techniques.
Results: In the absence of drug, radiation induced DNA-double strand breaks were almost completely repaired within 24-hours. In U87 both Tmz + IR, and SAHA + IR increased the olive moment compared to IR alone (24 hour post IR time-point). When Tmz and SAHA were combined together with IR, the olive moment decreased to 6.5 as compared to Tmz + IR alone 8.7 (p&lt;0.05). Similarly, in the absence of IR, SAHA was found to decrease Tmz induced DNA damage. Comparable results were obtained with gamma-H2AX assay and with the LN18 cell line. Clonogenic radiation survival assay demonstrated Tmz + SAHA to be no more effective than Tmz alone in potentiating the cytotoxic effect of IR. On qPCR, SAHA was found to down-regulate MLH1, MLH3, MSH2 and MSH 3, key genes involved in MMR.
Conclusions: Both Tmz and SAHA individually potentiated the effect of IR, inhibiting the repair of DNA double strand breaks. However, when cells were exposed to both drugs together less DNA damage was seen than with Tmz alone. Based upon qPCR data we hypothesize that SAHA down regulates the MMR pathway. Our work demonstrates that the addition of an HDAC inhibitor to cytotoxic agents may produce unexpected antagonism. Research sponsored by Merck.
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 5545.