bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 357: Induction of galectin-1 decreases radiosensitivity of patient-generated primary cell lines through AKT activation
Authors: Siedow Mike , Chakravarti Arnab , Lautenschlaeger Tim 
Published: February 2011

Abstract
Glioblastoma, grade IV malignant glioma based on the WHO classification, is one of the most common brain tumors found in adults and has an average survival time of twelve to sixteen months. The dismal prognosis associated with these tumors is largely due to their ability to grow and proliferate despite radiotherapy, which along with resection and Temozolomide is the current standard of care. A better understanding of the molecular mechanisms that define this malignant phenotype may result in new therapeutic targets and lead to improvements in how patients are treated. Galectin 1(GAL1), a beta-galactosidase binding protein, is strongly expressed in a variety of human cancers and has been shown to be upregulated by irradiation. In this study, we investigated the role of GAL1 upregulation following irradiation in a variety of patient-generated primary cell lines and its role in cell survival. Patient-generated primary cell lines were characterized using a variety of assays such as MTS, Annexin V, and cell viability. Western Blot analysis was performed probing for a variety of proteins implicated in proliferation, motility, and apoptosis. Radiation sensitivities were established by performing Clonogenic Survival Assays comparing the surviving fraction of patient-derived cell lines with established stable cell lines. 6 Gy irradiation upregulated Galectin 1 protein levels in the majority of primary cells used in our study. Furthermore, cell lines which Gal1was upregulated also displayed induction of Phospho-AKT and were significantly less sensitive to irradiation. The combination of GAL1 upregulation and Phosho-AKT induction following irradiation was associated with a significant decrease in the radiosensitization of the patient-derived primary cell lines used in our study. Interestingly, the patient-derived cell lines which showed no upregulation of GAL1 or Phospho-AKT induction displayed markedly increased sensitivity to radiation elucidating an interesting association between GAL1, Phospho-AKT, and radiation-sensitivity. The underlying mechanism by which GAL1 may medicate radioresistence seems to be through AKT activation, a well-documented protein involved in cell survival. Additional studies are ongoing to validate Galectin 1 as a target for radiation sensitization.
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 357.
Abstract 3578: New Angiochem-modified doxorubicin with increased brain penetration and efficacy against brain tumors
Authors: Demeule Michel , Régina Anthony , Yang Goagiang , Ché Christian , Béliveau Richard , Castaigne Jean-Paul 
Published: February 2011

Abstract
The blood-brain barrier (BBB) is mainly formed by brain capillary endothelial cells which are closely sealed by tight junctions and express high levels of active efflux transport proteins, including P-glycoprotein (Pgp). As a result, the overwhelming majority of small molecules, proteins and peptides do not cross the BBB. Angiochem's engineered peptide compounds (EPiC) provides a non-invasive and flexible platform for small and large molecules to treat brain diseases. Based on these properties, we have created a portfolio of new drug entities composed of siRNA, peptides and mAbs, the most advanced of which is ANG1005 formed by chemical conjugation of our peptide to three molecules of paclitaxel. ANG1005 demonstrated safety and efficacy in two phase ½ clinical trials for the treatment of primary and secondary brain tumors in humans. In the present study, we have investigated the brain uptake of a new chemical entity formed by conjugation of the peptide Angiopep-2 (An2) with 3 molecules of the anti-cancer drug doxorubicin. Despite the clinical effectiveness of doxorubicin in the treatment of many malignant tumors, clinical trials involving systemic administration have demonstrated very limited efficacy in the treatment of gliomas. This limited efficacy can be explained by the poor penetration of the drug thru the BBB and by the effect of the multidrug resistance pump, P-gp. Here, we show by mice in-situ brain perfusion that the ANG-doxorubicin (ANG1007) is transported very efficiently across the BBB. The transport rate is higher than that of unconjugated doxorubicin by at least 10-fold. In vitro, ANG1007 inhibits cancer cell proliferation, with highly cytotoxic activities against various tumor cell lines. In addition, brain perfusion studies performed with P-gp knock-out mice showed that ANG1007 bypasses the drug efflux pump P-gp at the BBB. Furthermore, ANG1007 inhibits growth of glioblastoma s.c. tumors and increases survival of mice implanted with brain tumors. In conclusion, these data confirm that conjugation of chemotherapeutic drugs such as doxorubicin to the peptide Angiopep-2 significantly enhances their entry into the brain and further validate the use of Angiochem's technology for new brain tumor therapies.
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 3578.
Abstract 3582: In vitro pharmacological studies of water soluble garlic extract (WSGE) in the management of acute promyelocytic leukemia (APL)
Authors: Yedjou Clement G. , Tchounwou Paul B. 
Published: February 2011

Abstract
Garlic (allium sativum) is one of the oldest cultivated plants, used in spices, food, and herbal medicine for over 4000 years. The therapeutic efficacy of garlic has a wide variety of ailments, including cardiovascular, cancer, hepatic and microbial infections. Although the therapeutic efficacy of garlic in the prevention of cancer and other diseases has received increasing attention in recent years, little is known about its mechanism for therapeutic action. In this research, we hypothesize that the pharmacological effect of garlic may be mediated through oxidative stress, DNA damage, modulation of annexin-5 and caspase-3 in human leukemia (HL-60) cells. To test this hypothesis, HL-60 cells were treated with various doses of water soluble garlic extract (WSGE) for 12 h. Cell survival was determined by MTT-assay. The extent of oxidative cell/tissue damage was determined by measuring the level of malonaldiahyde (MDA) concentrations. Cell apoptosis was measured by flow cytometry using annexin V and caspase-3 kits, respectively. MTT assay indicated a strong dose-response relationship with regard to the cytotoxic efficacy of WSGE in HL-60 cells. There was a slight increase in MDA concentrations in WSGE-treated cells compared to the control, but this was not statistically significant (P &gt; 0.05) probably due to the antioxidant property of garlic. WSGE-induced apoptosis was characterized by a significant (P &lt; 0.05) increase in the percentages of annexin-5 and caspase-3 positive cells. In summary, the pharmacotherapy of WSGE may be associated through induction of moderate toxicity, induction of DNA damage, phosphatidylserine externalization and caspase-3 activation characteristic of apoptosis.
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 3582.
Abstract 3584: Comparison of the severity of imatinib-induced cardiotoxicity in normotensive Sprague-Dawley (SD) and spontaneously hypertensive (SHR) rats
Authors: Herman Eugene H. , Knapton Alan , Rosen Elliot , Zhang Jun , Lu Quynh A. , Estis Joel , Todd John , Lipshultz Steven 
Published: February 2011

Abstract
Imatinib (IMNB) is a promising type of chemotherapeutic agent that specifically targets tyrosine kinase pathway-dependent tumors. However, cardiotoxicity has been reported with clinical use of IMNB. The characteristics of IMNB-induced cardiac alterations are not completely defined. The present study sought to examine the influence of a concomitant disease such as hypertension on the cardiotoxic effects of IMNB. Groups of adult male SD or SHR were dosed with 50 (5/group) or 100 mg/kg (10/group) IMNB or water (10/group)(p.o.) daily for 14 days (dose of 50 mg/kg is approximately 2x recommended human dose of 600 mg/m2). Tissues and blood samples were collected 24 hours after the last dosing. The 100 mg/kg dose caused a slight reduction in the rate of body weight gain. Serum levels of glucose were decreased and alanine transaminase (ALT) were increased in both SD and SHR dosed with IMNB. Changes from control were most pronounced in SD given 100mg/kg IMNB (ALT=175% vs 118% and glucose=81% vs 91% compared to SHR). White blood cell counts were depressed in SHR but not in SD rats. Dose-dependent cardiac lesions were noted in the groups of SD and SHR given either dose of IMNB (blinded evaluation). Cardiac lesions were characterized by cytoplasmic vacuolization, myofibrillar loss, interstitial infiltration with chronic inflammatory cells and fibrosis (proliferation of myofibroblasts). Mean lesion scores (based on a scale of 0 to 3) were higher in SHR than in SD (100mg/kg-1.9 vs 1.25 and 50 mg/kg-1.5 vs 1.1, p&lt;0.05)(Tukey-Kramer test). Increased serum levels of cardiac troponin I were detected in all IMNB-treated groups. The overall mean cTnI levels were higher in SHR (31.5, 41.3 and 53.9 pg/ml) compared to SD (6.8, 25 and 30 pg/ml) at the vehicle control, 50 and 100 mg/kg doses, respectively. These results indicate that hypertension as expressed in SHR appears to be a factor that can intensify the cardiotoxic effects of IMNB and that monitoring for cardiac troponin I may provide a sensitive means of detecting IMNB toxicity.
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 3584.
Abstract 3594: Development of a TRPV1 inducible expression model in MCF-7 breast cancer cells and its potential role in the evaluation of calcium channels as viable therapeutic targets in cancer
Authors: Wu Tina , Robinson Jodie , Monteith Gregory R. , Roberts-Thomson Sarah J. 
Published: February 2011

Abstract
Calcium is an important intracellular messenger that regulates many physiological functions such as cellular differentiation, proliferation and apoptosis. Abnormal functioning of calcium signaling pathways may occur during tumorigenesis. Calcium signals are tightly controlled by calcium influx channels and many calcium channels, including those of the transient receptor potential (TRP) ion channel family have altered expression levels in specific cancer types, such as the upregulation of TRPM8 in some prostate cancers. Plasma membrane calcium channels belong to a protein class that can be effectively pharmacologically modulated. Pharmacological agents are available that modify specific TRP calcium channels and some voltage gated calcium channels, such as the inhibition of L-type calcium channels by the anti-hypertensive nifedipine. Both activators and inhibitors of calcium channels overexpressed in cancer cells are potential anti-cancer drugs. This is due to the duality of the calcium signal, whereby calcium can be both a promoter of proliferation but also an inducer of apoptosis. Therefore, calcium channels with increased expression and/or activity in cancer could potentially serve as anti-cancer therapeutic targets. To test this and to explore some of the likely issues related to calcium channels as drug targets in cancer, we have generated a Tet-Off inducible model system where the transient receptor potential vanilloid 1 (TRPV1) calcium channel is over-expressed in the MCF-7 Tet-Off breast cancer cell line. TRPV1 has been chosen in this model, due to the wide availability of selective inhibitors and activators to this channel. TRPV1 functional activity in the model system was measured by calcium influx using the Fluorescent Imaging Plate Reader (FLIPR) and the calcium sensitive probe Fluo-4. Capsaicin, a TRPV1 agonist had an EC50 of 2 × 10-7 M for increased cytosolic free calcium in the absence of doxycycline and an EC50 of 1 × 10-6 M in the presence of doxycycline (1µg/ml). In this same stable cell line, peak cytosolic responses were significantly higher in the absence of doxycycline compared to the presence of doxycycline. This suggests a tight regulation of TRPV1 expression in the Tet-Off system. Future studies will characterize the consequences of TRPV1 over-expression and TRPV1 pharmacological modulators on cellular proliferation and apoptosis pathways. This model system could be an important tool to address the feasibility of calcium channels as drug targets 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 3594.
Abstract 3596: Comparison of intravenous microdialysis sampling to standard blood sampling to determine free etoposide exposure in non-human primates
Authors: Pastakia Devang , McCully Cynthia , Cole Diane , Bacher John , Cruz Rafael , Blakeley Jaishri , Widemann Brigitte , Balis Frank , Fox Elizabeth 
Published: February 2011

Abstract
Background: Microdialysis (MD) is a method for continuously sampling small molecules in tissue extracellular fluid in vivo. To determine if free (non-protein bound) drug exposure (AUC) in plasma could be accurately measured by MD under non-steady state conditions, we compared intravenous MD to standard serial plasma sampling during and after a short infusion of etoposide. Methods: CMA IView 64 catheters (10 mm PAES membrane with 20 kD MWT cutoff) were surgically implanted into the external jugular vein of Rhesus monkeys (Macaca mulatta). Catheter inflow and outflow tubing was tunneled subcutaneously from neck to the area on back between shoulder blades, brought through skin and attached to a MD pump (CMA 106 pump with fixed flow rate of 0.3 μL/min). The MD pump was secured in a fitted mesh jacket on the dorsum of the awake animal. Retrodialysis using 10 µM etoposide was used to measure in vivo relative recovery (RR) in each catheter. Following retrodialysis and catheter re-equilibration with normal saline, etoposide (5 mg/kg) was administered IV over 1 h. Serial plasma samples were collected during the infusion and for 8 h post-infusion. Free etoposide was extracted by ultrafiltration. MD samples were collected continuously over a single collection interval (0-9 h) or split into two collection intervals (0-3 h and 3-9 h). Etoposide was quantified using HPLC-electrochemical detection (linear range 0.05 - 10 μM). The etoposide concentration in MD samples was corrected for in vivo RR. The AUC was calculated by the linear trapezoidal method for serial plasma sampling and by summation of the concentration x time intervals for MD. Results: Simultaneous MD and serial plasma sampling was performed in 5 animals. The in vivo RR of etoposide ranged from 86.9 - 99.4%. The mean AUC0-9h for plasma free etoposide was 3.27 (median 3.81, range 2.11 - 5.15) μM·h. The mean AUC0-9h for MD sampling was 2.68 (median 3.02, range 1.75 - 3.65) μM·h. The mean ratio of AUCMD:AUCplasma was 0.81. The mean (95% CI) for the difference in the paired MD and plasma AUC was − 0.7 (−1.94, 0.54) µM·h. Conclusions: Quantitative MD sampling for pharmacokinetic studies is feasible and the in vivo RR of etoposide is high. Free etoposide exposure by MD slightly underestimates the AUC compared to serial plasma sampling. Intravenous MD sampling may be a promising alternative to standard plasma sampling for calculating free etoposide exposure.
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 3596.
Abstract 3599: The plasma and cerebrospinal fluid pharmacokinetics of satraplatin after intravenous administration in non-human primates
Authors: Marcus Leigh J. , Murphy Robert F. , Fox Elizabeth , McCully Cynthia L. , Cruz Rafeal , Warren Kathy , Balis Frank M. , Widemann Brigitte C. , Meyer Thorsten 
Published: February 2011

Abstract
Background: Satraplatin is an orally bioavailable platinum analog with preclinical activity (IC50 range in tumor cell lines 0.04 - 16 µM) in cisplatin sensitive and resistant models and clinical activity in adults with refractory cancers including prostate cancer. The cerebrospinal fluid (CSF) penetration of cisplatin and carboplatin in non-human primates (NHP) is limited (3.6% and 3.8%, respectively). We evaluated the plasma and CSF pharmacokinetics (PK) of satraplatin, which is more lipophilic than other platinum analogs, after an intravenous (IV) dose in a NHP model. Methods: Satraplatin 120 mg/m2 was administered as 1 h IV infusion in DMSO (5%) and normal saline to 5 NHP. Serial blood and CSF samples were obtained over 48 hours. Plasma was separated immediately and ultrafiltrate (UF) was prepared by centrifugation through a Microcon 10K MWCO filter. CSF was obtained from an indwelling Ommaya reservoir (n=4) or from a temporary lumbar catheter (n=1). Platinum was quantified in the plasma UF and CSF using a validated atomic absorption spectroscopy assay with lower limit of quantification of 0.03 µM in UF and CSF. Pharmacokinetic parameters were estimated using non-compartmental analyses. CSF penetration was calculated from the AUCCSF:AUCPlasma. Results: Satraplatin was well tolerated by all NHP. Pharmacokinetic parameters (median and range) for satraplatin plasma UF were Cmax 8.3 (5.7-10.6) µM, AUC0-48h 28.3 (22.6-33.2) µM·h, AUC0-inf 34.2 (24.7-38.2) µM·h, clearance 3.6 (2.4-4.3) L/h, and t1/2 18.8 (13.4-25) h. Satraplatin was detected in the CSF of all NHP. For the 4 NHP with Ommaya reservoirs PK parameters were: tmax 1.5 (1.3-2.1) h from the start of infusion, Cmax 0.07 (0.02-0.12) µM, AUC0-48h 1.2 (0.49-2.43) µM·h, ratio AUC0-48h CSF:AUC0-48h Plasma was 4.3 (2.2-7.4) %. For the NHP with lumbar catheter and limited CSF samples the tmax was 1.1 h, and Cmax was 0.62 µM. Conclusions: Satraplatin penetration into CSF is similar to that of carboplatin and cisplatin, despite its greater lipophilicity. The development of a phase I trial of satraplatin for refractory childhood solid tumors including brain tumors is in progress.
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 3599.
Abstract 360: Tamoxifen treatment induces mitogen-activated protein kinase phosphatase-1 expression in T47D breast cancer cells
Authors: Haagenson Kelly K. , Peng Dongjun , Wu Gen Sheng 
Published: February 2011

Abstract
Mitogen Activated Protein Kinase Phosphatase-1 (MKP-1) is a dual specificity phosphatase known to target the Extracellular Signal Regulated Kinases (ERK), c-Jun N-terminal Kinases (JNK) and the p38 Mitogen Activated Protein Kinases (p38), which make up the Mitogen Activated Protein Kinase (MAP Kinase) family. These pathways play vital roles in determining whether cells continue to survive or undergo apoptosis. ERK mainly contributes to cell survival while JNK and p38 signaling can be involved in both cell survival and apoptosis. The function of MKP-1 is to attenuate the signals perpetuated by ERK, JNK and p38. Previous research in our lab has shown that knockdown of either MKP-1 or ERK-2 leads to increased cisplatin sensitivity in ovarian cancer. ERK activation has also been linked to tamoxifen resistance and poor prognosis in breast cancer, but the effects of MKP-1, JNK and p38 in this area are not well studied. A previous study by Cui et al has shown that overexpression of MKP-3, which mainly targets ERK, increased tamoxifen resistance in breast tumors. We chose to focus this investigation on the contribution of MKP-1 to tamoxifen resistance because of its ability to dephosphorylate all three MAP Kinase family members. In our study, MKP-1 protein expression was shown to be elevated in MDA-MB-231, T47D and MCF7 breast cancer cells as compared to non-malignant MCF10A cells. After four and six hours of treatment with 1 μM tamoxifen, MKP-1 protein expression was increased in T47D cells compared to untreated parental control cells. Very little change in phosphorylated ERK protein levels was observed at these same time points. There were, however, decreases in phosphorylated JNK protein levels after four and six hours of 1μM tamoxifen treatment when compared to untreated parental control cells. Since some chemotherapeutic agents induce apoptosis in a JNK mediated manner, a decrease in JNK expression in tamoxifen treated breast cancer cells could contribute to decreased therapeutic efficacy. In conclusion, by examining changes in protein expression levels in tamoxifen treated breast cancer cells we have identified that increased MKP-1 expression leads to a decrease in phosphorylated JNK expression. This finding could constitute a mechanism contributing to tamoxifen resistance in estrogen receptor positive breast cancer cells and suggests that modulation of MKP-1 expression could increase tamoxifen sensitivity in these cells.
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 360.