bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2495: The autophagy inducing drug carbamazepine is a radiation protector and mitigator
Authors: Kim Hyun , Bernard Mark , Flickinger John , Epperly Michael W. , Wang Hong , Dixon Tracy M. , Shields Donna , Houghton Frank , Greenberger Joel S. 
Published: June 2012

Abstract
The role of autophagy in cellular response to radiation is controversial. Some investigators report that induction of autophagy increases radiosensitivity whereas others report that it confers radioresistance. Carbamazepine, traditionally used to treat mood disorders, epilepsy and trigeminal neuralgia, has recently been shown to induce autophagy. We hypothesized that carbamazepine would be radioprotective in vitro and in vivo by upregulating autophagy in cells and tissue after irradiation. In clonogenic assays of murine hematopoietic progenitor cells (32Dcl3), carbamazepine at 1, 10 and 100 uM for 1 hour prior to irradiation (0 – 8 Gy) increased the Do from 1.5 ± 0.1 to 2.1 ± 0.1 (p = 0.011), 2.3 ± 0.1 (p = 0.010), and 3.6 ± 0.7 (p = 0.003), respectively. Carbamazepine after irradiation increased the shoulder (ñ) on the survival curve from 1.4 ± 0.3 to 10.1 ± 4.2 (p = 0.011), 5.5 ± 1.7 (p = 0.018), or 3.6 ± 0.8 (p = 0.014), respectively. C57BL/6NHsd mice with intraperitoneal injection of carbamazepine (20 mg/kg) immediately before or after 9.25 Gy irradiation demonstrated increased survival (p = 0.008 and 0.005, respectively). JC1 stain and TUNEL assay revealed that carbamazepine had no effect on changes in mitochondria potential or apoptosis, respectively, following 5 or 10 Gy. Immunoblot for LC3 in 32Dcl3 cells 24 hours after irradiation revealed a 3.3x (5 Gy) and 6.2x (10 Gy) increase in LC3II/LC3I when cells were incubated in 50 uM carbamazepine. Cells irradiated in the absence of carbamazepine exhibited a 1.3x (5 Gy) and 1.8x (10 Gy) LC3II/LC3I increase, respectively. This data suggest that carbamazepine may be a valuable radiation mitigator by upregulating autophagy in irradiated cells.
Supported by 2U19A1068021-06
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 2495. doi:10.1158/1538-7445.AM2011-2495
Abstract 250: The critical requirement of ATM function in PTEN null cell lines
Authors: McCabe Nuala , Walker Steven M. , Greenan Caroline , Wikstrom Katarina , McLean Estelle , Delaney Thomas , McCarthy Michelle , James Iain , Harrison Timothy , Mullan Paul , Harkin Paul , Kennedy Richard 
Published: June 2012

Abstract
Introduction: The tumour suppressor PTEN is frequently lost in multiple cancer types, loss of PTEN function has been linked to activation of the AKT signalling pathway. The regulation of the AKT signalling has long been attributed as the key tumour suppressing function of PTEN. However, it has recently been demonstrated that PTEN null cells demonstrate genomic instability and require base excision repair (BER) for survival. One of the critical functions of BER is the repair of oxidative DNA damage; we postulated that PTEN might have a role in the maintenance of this form of damage. Additionally, we investigated which molecular pathways were involved in the response of this form of DNA damage in PTEN null cells.
Results: Using isogenic cell lines we found an increased in baseline ROS levels according to PTEN status. Specifically the increase in ROS levels was correlated to an increase in the levels of double strand breaks as measured by levels of activated γH2AX, formation of γH2AX foci and activation of the DNA damage response kinase ATM. Furthermore, inhibition of ATM function both via siRNA knockdown and small molecule inhibition in PTEN null cells resulted in cell cycle arrest followed by apoptosis. Strikingly this dependence on ATM activity was independent of AKT activity, suggesting that the oxidative DNA damage was the result of a loss in PTEN function independent of its role in the regulation of the AKT activation.
Conclusions: These observations suggest that PTEN may play a role in the maintenance of the repair of ROS DNA damage; furthermore it maybe postulated that inhibition of ATM maybe a suitable therapeutic intervention for PTEN null tumours.
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 250. doi:10.1158/1538-7445.AM2011-250
Abstract 2502: Swallowed small molecule GS-nitroxide, JP-4-039, protects the irradiated esophagus
Authors: Epperly Michael W. , Greenberger Joel S. , Kim Hyun , Bernard Mark , Dixon Tracy , Franicola Darcy , Wipf Peter , Li Song , Gao Xiang , Kagan Valerian , Amoscato Andrew , Shen Hongmei 
Published: June 2012

Abstract
Irradiation induced esophagitis is a dose limiting factor in the treatment of lung cancer, and limits irradiation dose escalation. Intraesophageal manganese superoxide dismutase plasmid liposomes has been shown to protect against irradiation esophagitis (Tarhini, et.al. Human Gene Therapy, in press). A new small molecule drug recently has shown irradiation protection and mitigation in vitro. The new drug (JP4-039) is a nitroxide attached to a mitochondrial targeting sequence. Drug was delivered to the top of the esophagus and the mouse swallowed the F15 formulation, consisting of soy PC: Tween-80: L-glutamyl dioleylamide (4:1:1 w/w) and 8 mg/ml of JP4-039 in PBS. C57BL/6NHsd mice swallowed 100 µl water followed by 100 µl F15-JP4-039 (0.4 mg/mouse) ten minutes before 28 Gy to the upper body. F15-JP4-039 resulted in a significant increase in survival compared to irradiated controls. F15-JP4-039 produced a 30 day survival of 75% compared to 30% for irradiation control (p = 0.0315). The JP4-039 nitroxide signal, detected by EPR, allowed demonstration that drug was in whole esophagus and in the esophageal stem cells. F15-JP4-039 intraorally treated mice were sacrificed at 10 min, 30 min, 1 hr or 5 hr after swallowing the F15-JP4-039, esophagus removed, single cell suspensions made, frozen, and analyzed by EPR. At 10 min, 2971.3 fmoles of JP4-039/million cells were detected, and still detected out to 5 hours, 1081 fmoles/million cells, after irradiation. Sorted side population cells (SP), enriched for stem cells, and nonside population cells (NSP) isolated by flow cytometer were analyzed at 10 min after swallow, by EPR for JP4-039 uptake. The SP cells had 3666.7 fmoles per million cells and the NSP cells had 73.7 fmoles nitroxide per million cells demonstrating that drug had reached stem cells. Thus, intraesophageal administration of small molecule antioxidant GS-nitroxide reduces murine radiation esophagitis, and may be a valuable translational radiation protector to ameliorate clinical esophagitis in lung cancer patients.
Supported by 2U19A1068021-06 and RO1-CA83876-06
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 2502. doi:10.1158/1538-7445.AM2011-2502
Abstract 2507: Triple agent therapy combining radiation with AMG479 (IGF1R antibody) and panitumumab (EGFR antibody) in a head and neck tumor model
Authors: Matsumoto Fumihiko , Raju Uma , Valdecanas David , Milas Luka , Ang K Kian 
Published: June 2012

Abstract
PURPOSE: The combination of radiation with concurrent chemotherapy improves local-regional control and overall survival in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). However, its acute and chronic toxicity have raised concerns and thereby prompted the search for more biologically sound therapeutic strategy, e.g., targeting receptor tyrosine kinases (RTKs) that are differentially expressed between tumors and normal tissues. The current study tested the therapeutic benefits of co-targeting two RTKs, namely, epidermal growth factor receptor (EGFR) by panitumumab (Pmab) and insulin-like growth factor receptor-1 (IGF-1R) by AMG479 to enhance tumor response to radiation.
METHODS AND MATERIALS: A HNSCC model, FaDu, was used for assessing the effects of AMG479, and Pmab to improve tumor response to radiation by in vitro clonogenic cell survival assay and in vivo tumor growth delay assay. Various doses and administration scheduling of these agents relevant to radiation were tested.
RESULTS: In vitro study showed that Pmab significantly enhanced the radiosensitivity of FaDu with an enhancement factor (EF) of 1.4 at 0.5 survival fraction. AMG479 given alone or concurrently with Pmab had no affects in normal (10% serum) culture media. In vivo xenograft studies showed that Pmab or AMG479 given as single agent enhanced the tumor response to fractionated radiation (2 Gy twice a day for 6 d) in a dose and schedule dependent manner. The maximum EF was 1.1 for AMG479 and 1.7 for Pmab. The effects of combining Pmab and AMG479 with radiation depended markedly on the scheduling. The best effects were achieved when (1) Pmab and AMG479 were given concurrently daily starting 4 d before radiation for a total of 15 days resulting in an EF of 3.0 or (2) Pmab and AMG479 were given sequentially commencing Pmab 4 d before radiation for 15 d and AMG479 after completion of radiation also for 15 d yielding an EF of 2.9. However, administering AMG479 before radiation followed by Pmab was much less effective (EF: 2.0).
CONCLUSIONS: Our results showed Pmab enhanced FaDu response to radiation. AMG479 markedly increased tumor response when given together or following Pmab, in conjunction with radiation. These findings provide the rationale for clinical testing of the combination of Pmab and AMG479 for the treatment of HNSCC along with the most promising regimen of administration.
Supported by Amgen Inc., Thousand Oaks, CA
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 2507. doi:10.1158/1538-7445.AM2011-2507
Abstract 2508: Identification of potential relevant pathways and genes for resistance to chemoradiotherapy in colorectal cancer cells
Authors: Grade Marian , Spitzner Melanie , Emons Georg , Kramer Frank , Gaedcke Jochen , Rave-Fränk Margret , Scharf Jens-Gerd , Burfeind Peter , Becker Heinz , Beissbarth Tim , Ghadimi B. Michael , Ried Thomas 
Published: June 2012

Abstract
The standard treatment of patients with locally advanced rectal cancers comprises preoperative 5-fluorouracil-based chemoradiotherapy followed by standardized surgery. However, the tumor response to multimodal treatment has varied greatly and ranging from complete resistance to complete pathologic regression. The prediction and treatment of these observed heterogeneous response to therapy in patients is, therefore, an important clinical need.
A strategy for studying the molecular basis of this heterogeneous tumor response is to establish the clinical parameters as an in vitro model. For this purpose we used 12 colorectal cancer cell lines and exposed them to 3 µM of 5-fluorouracil and 2 Gy of radiation, which reflect the parameters used in clinical patient treatment. The sensitivity differences of the cell lines to chemoradiotherapy, measured as surviving fractions by a standard colony formation assay, were then correlated with the pretherapeutic gene expression profiles of these cell lines. The microarray measurements were independently validated for a subset of these genes using real-time polymerase chain reactions.
In the 12 colorectal cancer cell lines we observed a heterogeneous response, with surviving fractions ranging from 0.28 to 0.81, closely recapitulating clinical reality. Using a linear model analysis, we identified 4,796 features whose expression levels correlated significantly with the sensitivity to chemoradiotherapy (Q &lt; 0.05), including many genes involved in the mitogen-activated protein kinase signaling pathway or cell cycle genes. These data have suggested a potential relevance of the insulin and Wnt signaling pathways for the treatment response, and we identified STAT3, RASSF1, DOK3, and ERBB2 as potential therapeutic targets.
We anticipate that this analysis of a gene expression signature for the in vitro chemoradiosensitivity of colorectal cancer cells will unveil molecular biomarkers predictive of the response of rectal cancers to chemoradiotherapy and enable the identification of genes that could serve as targets to sensitize a priori resistant primary 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 2508. doi:10.1158/1538-7445.AM2011-2508
Abstract 251: Kinome-wide RNAi screen identification of synthetic lethal interactions in BRAF-mutant melanoma
Authors: Zejnullahu Kreshnik , Wagenaar Tim , Green Michael R. 
Published: June 2012

Abstract
BACKGROUND. Mutations in the BRAF oncogene are prevalent in many types of solid cancers, where they promote cell proliferation and transformation by constitutively activating the RAF-MEK-ERK signaling pathway. Inhibitors of BRAF have been developed as potential cancer therapies but unfortunately many have performed poorly in clinical trials. As an alternative approach, we performed RNA interference (RNAi) screening to identify genes that are synthetically lethal with the BRAF-mutant oncogene in malignant melanoma cell lines. Recent advances in RNAi and deep sequencing technologies have made it possible to systematically interrogate the genome for synthetic lethal interactions.
METHODS. Two BRAF-mutant melanoma cell lines (SKMEL28 and Malme3M) and one wild-type BRAF cell line (MeWo) were infected with a subset of The RNAi Consortium (TRC) shRNA library comprising all the kinases in the human genome as well as the genes involved in the tyrosine kinase&gt;RAS&gt;RAF&gt;MEK&gt;ERK pathway. Cells were collected at 4 and 19 days post-infection, genomic DNA was isolated, shRNAs were PCR amplified and subjected to massively parallel sequencing. Statistical analysis identified ∼200 shRNAs that were selectively depleted in BRAF-mutant but not wild-type BRAF cell lines; individual canidate shRNA were tested in a panel of 6 melanoma cell lines 3 BRAF-mutant (UACC62, UACC257, Malme3M) and 3 wild-type BRAF (WM3912, WM3918, MeWo).
SUMMARY. The screen identified a diverse number of genes that are synthetically lethal with the BRAF-mutant oncogene in human malignant melanoma. Not surprisingly, a number of the identified synthetic lethal genes are known downstream effectors of BRAF or known scaffold proteins involved in MAPK signaling. Paradoxically, epiregulin (EPGN), a known ligand of the epidermal growth factor receptor (EGFR) and EGFR itself, which are upstream of the BRAF oncogene were also identified in the screen as synthetically lethal with mutant BRAF.
CONCLUSIONS. The BRAF oncogene is synthetically lethal with genes involved in diverse cellular processes such as kinase signaling, cell division, nuclear shuttling and cell metabolism. Many of the genes identified in the RNAi screen are known effectors of the MAPK cascade. Paradoxically, two members of the MAPK cascade, EGFR and its ligand EPGN, both of which are upstream of BRAF, were identified in the screen and validated to be synthetically lethal with mutant BRAF.
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 251. doi:10.1158/1538-7445.AM2011-251
Abstract 2512: Combining radiation or carboplatin with targeted inhibition of survivin increases treatment induced apoptosis in retinoblastoma cells
Authors: Luna Marian , Ferrario Angela , Rucker Natalie , Wong Sam , Gomer Charles J. 
Published: June 2012

Abstract
The overarching goal of this project is to evaluate clinically relevant protocols to improve treatment responses for retinoblastoma (Rb). Procedures to treat Rb vary depending on the size and location of the intraocular lesions and can include carboplatin or radiation therapy. We have preliminary data documenting over expression of survivin, a member of the inhibitor of apoptosis family of proteins, following treatment of Rb cells with either carboplatin or ionizing radiation. The specific aim of the current study is to determine if targeted inhibition of survivin expression using the clinically relevant small molecule imidazolium inhibitor, YM155, can increase selective cytotoxicity in Rb cells. Experimental procedures used Y79 retinoblastoma and RPE normal retinal pigmented epithelial cell lines. Protein expression following either single or combined treatment protocols is examined by Western immunoblot. Levels of apoptosis and cytotoxicity are determined by flow cytometry following Annexin V and propidium iodide staining. We document that both radiation (5 Gy) and carboplatin (5 uM) induce significant over expression of survivin in Y79 cells, but not in RPE cells. Over expression of survivin following radiation or carboplatin is blocked in Y79 cells exposed to YM155 (2 nM). Combining radiation or carboplatin with YM155 resulted in significantly increased levels of apoptosis and cell killing in Y79 cells but not in RPE cells. These results indicate that targeted inhibition of survivin may provide a therapeutic gain when combined with radiation or carboplatin.
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 2512. doi:10.1158/1538-7445.AM2011-2512
Abstract 2515: Inverse relationship between PSA and IL-8 in prostate cancer: An insight into the mechanisms of NF-κB-mediated radioresistance
Authors: Xu Yong , Fang Fang , Clair Daret K. St. , Clair William H. St. 
Published: June 2012

Abstract
Nuclear factor κB (NF-κB), an inflammatory responsive transcription factor, is involved in tumorigenesis and resistance of cancer cells to therapy-induced cytotoxicity. Our previous studies demonstrated that activation of RelB-mediated NF-κB alternative pathway contributes to tumorigenicity of prostate cancer, decreased the circulating levels of prostate specific antigen (PSA), and enhanced the level of interleukin-8 (IL-8). The present study extends to directly test the role of RelB on radioresistance of prostate cancer in vivo, investigate the relationship between IL8 and PSA expression, and determine their role in the response of prostate cancer to radiation. We found that expression of RelB in prostate cancer cells with a low basal level of RelB (LNCaP) reduced their radiosensitivity and suppression of RelB in prostate cancer cells with a high basal level of RelB (PC3) enhanced their radiosensitivity in vitro and in xenograft tumors. The RelB-mediated inverse relationship between PSA and IL-8 expression was verified through direct modulation of RelB levels by transfection of RelB cDNA and RNAi in multiple prostate cancer cell lines. Interestingly, when the cellular levels of PSA and IL-8 were manipulated, by treating cultural cells with pure compounds or genetic manipulations, we found that up-regulation of IL-8 with concurrent down-regulation of PSA reduced radiosensitivity of prostate cancer cells. In contrast, up-regulation of PSA with concurrence down-regulation of IL-8 resulted in an increase in radiosensitivity. Together, the results reveal a previously unrecognized role of IL-8 on PSA expression, identify an inverse relationship between PSA and IL-8 as an indicator of radiosensitivity and implicate inhibition of the NF-κB alterative pathway as a promising approach for prostate cancer treatment.
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 2515. doi:10.1158/1538-7445.AM2011-2515
Abstract 2518: Structure-activity relationships of folate-vinca alkaloid conjugates
Authors: Leamon Christopher P. , Vlahov Iontcho R. , Reddy Joseph A. , Vetzel Marilynn , Santhapuram Hari K. , You Fei , Bloomfield Alicia , Dorton Ryan , Nelson Melissa , Kleindl Paul , Vaughn Jeremy , Westrick Elaine 
Published: June 2012

Abstract
EC145 is a potent folate-targeted vinca alkaloid conjugate that has been evaluated in 2 single agent phase 2 trials (ovarian and non small cell lung cancers) and 1 randomized open labeled phase 2 study in combination with DOXIL® in women with platinum-resistant ovarian cancer. Results from all of these trials have looked promising, and they support the continued evaluation of EC145 in a planned phase 3 trial that's expected to begin in early 2011. Structurally, EC145 consists of 4 essential modules: 1) folic acid, 2) a hydrophilic peptide spacer, 3) a disulfide-containing, self-immolative linker, and 4) the microtubule destabilizer, desacetylvinblastine hydrazide (DAVLBH). Due to EC145's potential for success, recent effort was given to determine the impact of i) substituting the DAVLBH vinca alkaloid unit in EC145 with analogs of vincristine, vindesine or vinorelbine, ii) substituting the naturally (S)-configured Asp-Arg-Asp-Asp-Cys peptide spacer in EC145 with (R)-configured amino acids placed in selective locations, and iii) varying the composition of the linker module to evaluate the impact of having a readily releasable, self-immolative linker system (e.g. disulfide-based as found in EC145) versus a more stable linker system (e.g. a thioether). New conjugates were screened in vitro against folate receptor-positive cells, and their cytotoxic activities were directly compared to that produced by EC145. Our data show that only DAVLBH-containing folate conjugates were active; thus, conjugates built with vincristine, vindesine or vinorelbine failed to produce activity when cells were exposed to concentrations as high as 1 µM. Within the DAVLBH series, having a bio-releasable, self-immolative linker system was found to be critical for activity since multiple analogs constructed with thioether-based linkers failed to produce meaningful activity both in vitro and in vivo. Substitutions of some or all of the natural amino acids within EC145's hydrophilic spacer module was not found to significantly change the in vitro potency of the conjugate; however, some enhancement in anti-tumor activity was measurable when tested in vivo against well-established subcutaneous folate receptor-positive tumor xenografts. Despite these modest improvements, EC145 remains as one of the more potent folate-vinca alkaloid conjugates produced to date, and continued clinical development is therefore 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 2518. doi:10.1158/1538-7445.AM2011-2518