bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3694: The mitochondrial FAD-linked glycerol-3-phosphate dehydrogenase as an inhibitory target for cancer therapeutics
Authors: Paschos Athanasios , Laflamme Pierre , Singh Gurmit
Published: February 2011

The hypoxic and glycolytic environment of malignant cells facilitates high levels of reactive oxygen species (ROS) production. Breast, ovarian and prostate cancer etiology is associated with the ROS production, which are thought to play an important role in regulating the cancers cell growth, survival and metastasis. A potent and major cellular, however functional limited characterized source of ROS, is the mitochondrial FAD-linked glycerol-3-phosphate dehydrogenase (GPD2). GPD2 is an essential component of the glycerol-3-phosphate shuttle and necessarily expressed in all tissues. In several cancer cell lines, GPD2 is highly expressed and we estimated it accounts for up to 70% of the total ROS production within the prostate cancer cell line PC3. In this study we have utilized this knowledge, to complete a cell-based high throughput-screening (HTS) assay, aimed to identify small molecule inhibitors of the GPD2 dependent ROS formation in PC3 cell lines.

We employed the amplex red hydrogen peroxidase detection assay and adapted it to the HTS format. 133 inhibitory compounds from the Canadian Compound Collection were identified to reduce the ROS production activity within the PC3 cells. In order to validate these hits and to determine their mode of action, we PCR amplified GPD2 form PC3-cell cDNA and purified recombinant human GPD2 from a bacterial overproducing strain to homogeneity by employing Strep-tactin affinity-chromatography. The heterologously expressed enzyme, devoid of its mitochondrial target sequence, displayed glycerol-3-phosphate dependent resazurin, dichlorophenolindophenol, as well as tetrazole/phenazine methosulfate oxidoreductase activity. Follow up enzymatic assays of the primary HTS hits with the artificial electron acceptors identified several GPD2 activity specific inhibitors. Subsequent concentration response studies of the HTS derived inhibitors elucidated their in vitro half maximal inhibitory concentration at the range of 10 μM. In order to map GPD2's ROS production site and determine the inhibitor binding sites within the enzyme, we bioinformatically derived the proteins tertiary structure.

Considering that GPD2 dependent ROS formation may drive the prostate cancer proliferation, we aim by exploiting the results of this work to generate novel lead molecules as promising potential anti-proliferating cancer drug candidates.

(This work was supported by a grant from the Canadian Institutes of Health Research to Gurmit Singh)

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 3694.
Abstract 3698: Development of a hydrophobic docetaxel prodrug nanoparticle with enhanced plasma circulation lifetime and improved efficacy
Authors: Johnstone Sharon A. , Ansell Steven M. , Harasym Troy O. , Xie Sherwin , Mayer Lawrence D. , Tardi Paul
Published: February 2011

Amphiphilic block co-polymers can form highly stable micellar-nanoparticles which can be used to trap hydrophobic chemotherapeutic agents. While block co-polymer formulations effectively retain drugs in vitro, nanoparticles frequently display burst release of trapped agents upon injection into animals. As a result, nanoparticles often show only limited improvements in drug circulation lifetime and likely provide little improvement in drug delivery to the tumor site. To address this issue, we previously generated hydrophobic prodrugs of paclitaxel to enhance retention within the nanoparticle and observed a correlation between drug circulation lifetime and the hydrophobicity of the anchor. When these formulations were evaluated for anti-tumor efficacy, the longest circulating paclitaxel prodrugs were the most efficacious. We have now extended our assessment to hydrophobic docetaxel prodrug formulations and have related plasma circulation characteristics of the docetaxel prodrug nanoparticles to suppression of tumor growth in mice bearing HT-29 human colorectal tumor xenographs. Docetaxel-docosanyl diglycolate (procet 7), and docetaxel-cholesteryl diglycolate (procet 8) were formulated in PS-PEG nanoparticles at a drug:polymer weight ratio of1:2 and injected i.v. into mice. The plasma half-life of the docetaxel prodrug was enhanced relative to the corresponding paclitaxel prodrug and significantly greater than docetaxel formulated in polysorbate 80. When dosed at their respective maximum tolerated dose (MTD), docetaxel, procet 7 and procet 8 nanoparticles resulted in a tumor growth delay (TGD) of 66%, 213% and 241% respectively. In addition docetaxel prodrugs administered at equimolar doses to docetaxel displayed greater antitumor activity than the free drug (77% and 105% TGD for procet 7 and procet 8 nanoparticles respectively). We attribute the increased potency of docetaxel prodrugs over paclitaxel prodrugs to the extended plasma circulation lifetimes of the former. These results confirm that hydrophobic docetaxel prodrugs can be formulated into block co-polymer nanoparticles to achieve prolonged circulation kinetics which result in enhanced therapeutic activity.

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 3698.
Abstract 3701: A targeted delivery system for anticancer drugs based on functionalized carbon nanotubes
Authors: Heister Elena , Neves Vera , Silva Ravi P. , McFadden Johnjoe , Coley Helen M.
Published: February 2011

Carbon nanotubes have emerged as a promising nanomaterial for the development of customizable drug delivery system due to their ability to penetrate cell membranes and to attach high loads of drugs and targeting agents on their surface. In the field of oncology, this promotes the development of therapies with improved effectivity and fewer side effects by assisting the targeting of therapeutic agents to the desired site of action. Our work focuses on the targeted delivery of the anthracycline and anthracenedione anticancer drugs doxorubicin and mitoxantrone to human colon cancer cells (WiDr) by means of a carbon nanotube-based drug delivery system. The drugs are attached to the nanotube surface in a non-covalent manner, resulting in a weight ratio (drug: CNTs) of 4:1 owing to the high surface area of CNTs. As drug binding is higher at physiological pH than at a slightly acidic pH, this method allows for the release of the drug from the nanotubes in such environments, for example late endosomes and lysosomes. In a previous study, we have shown that doxorubicin-loaded carbon nanotubes are are taken up by WiDr colon cancer cells and release their drug payload upon cellular internalization, which then translocates to the nucleus [1]. Current work is focusing on the targeting aspect: to increase the specificity of our system, we further attach a monoclonal antibody to the nanotube carrier that recognizes/binds to carcinoembryonic antigen (CEA), a target structure overexpressed by WiDr colon cancer cells. In vitro cytotoxicity studies show that the targeted drug-CNT complexes indeed have a greater therapeutic effect on WiDr cells than on MCF7 breast cancer cells, which do not express CEA. Future work will include in vivo studies on mice bearing tumor xenographs to evaluate the feasibility and behavior of our system in a setting of clinical relevance.

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 3701.
Abstract 3708: Carbon nanotubes: Feasibility as nano-bio agents to target cancer
Authors: Neves Vera , Heister Elena , McFadden Johnjoe , Silva Ravi P. , Coley Helen M.
Published: February 2011

The targeting of genes in cancer cells to stop tumour growth and kill the cancer cells has emerged as a promising approach for cancer therapy. The key challenges for the application of this kind of approach are largely dependent on the development of suitable delivery systems. None of the current transfection methods are ideal, mainly because they often provoke immune responses. Recently, carbon nanotubes (CNTs) have been shown to transverse cellular membranes and shuttle biological molecules, including DNA, siRNA, and proteins into cancer cells. The main advantages of carbon nanotubes compared with other delivery agents are their biocompatibility and the large surface area.

To consider carbon nanotubes as nano-bio agents for gene therapy it is important first, understand how they behave at a cellular level. In our lab, we have carried out studies to determine the fate and trafficking of carbon nanotubes in cancer cells. Evidence of carbon nanotube uptake and release has been shown with no significant changes in cell components, such as DNA/RNA, proteins and lipids. Moreover, no significant stress was induced when cells were exposed to carbon nanotubes. Intracellular localisation and trafficking of carbon nanotubes was carried out by antibody staining of specific compartments within the cell and reveal that an endocytic pathway is involved on the internalisation of carbon nanotubes.

Finally, our work is currently focusing on the development of an in vitro model to examine the feasibility of using functionalized, CNTs as a means of delivering gene therapy using siRNA. We will then use this as a basis for further in vivo work using human tumour xenograft models with characterised genotypes (e.g. mutated p53 etc) to validate this approach.

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 3708.
Abstract 3709: Synthesis of chlorin-based fatty acid conjugate as photosensitizer for photodynamic therapy
Authors: Gantumur Battogtokh , Kim Sook Hee , Bae Sumi , Bae Su Jin , Kang Uk , Shick Ahn Woong
Published: February 2011

Photodynamic therapy (PDT) is promising an approach to cancer treatment that requires the combination of photosensitizer (PS), tissue oxygen, and light. Many PSs have been developed for the PDT; however, very few have made in clinical trials because improved drugs that are more selective and that can be used conveniently and without sustained skin photosensitivity are needed. Tumor targeting drug delivery is another attractive strategy in cancer treatment.

In this study, our purpose is to improve their selectivity on tumor cell as conjugating of chlorin-based PSs with unsaturated fatty acids (UFAs) that are taken up rapidly by tumors from the arterial blood, presumably for use as biochemical precursors and energy sources.

We have selected methyl pyropheophorbide-d-OH (MPPd) and pyropheophorbide-a-173-N-hexanol (PPa-N-He) that possess reactive hydroxyl groups for the molecule as developing photosensitizers, which were conjugated with docosahaxaenoic acid (DHA) and oleic acid (OA) by esterification reaction DCC-mediated, respectively, and gave in enough yield. Our selected PSs were obtained according to Tamiaki et al.1 and Smith et al.2 reported. Novel MPPd-DHA, MPPd-OA, PPa-N-He-DHA, and PPa-N-He-OA were prepared and structure of them was confirmed by spectroscopy's methods (1D and 2D NMR, UV-vis, and MS). The spectrum data of the compounds was clear and easy to characterize.

Our synthesized chlorin-based fatty acid conjugates that could be present a synergistic effect for PDT through a more accumulation of the conjugates on tumor cells due to both of those produce a reactive oxygen substrate (ROS). The conjugates have a high lipophilicity because the UFAs were linked to the PSs and the lipophilicity of PS has proven to be an important factor because it influences the biodistribution and clearance and thus the bioactivity of drugs.

References

1. Tamiaki, H.; Miyata, S.; Kureishi, Y.; Tanikaga, R. Tetraheddron. 1996, 52, 12421-12432.

2. Smith, K. M.; Goff, D. A.; Simpson, D. J. J. Am. Chem. Soc. 1985, 107, 4946-4954.

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 3709.
Abstract 3712: 2-Methoxyestradiol inhibits Barrett's esophageal adenocarcinoma growth and aggressive phenotypes through differential regulation of β-catenin-E-cadherin-axis
Authors: Kambhampati Suman , Banerjee Snigdha , Dhar Kakali , Mehta Smita , Haque Inamul , Dhar Gopal , Majumder Monami , Ray Gibanananda , Vanveldhuizen Peter J. , Banerjee Sushanta K.
Published: February 2011

The purpose of this study was to evaluate whether 2-methoxyestradiol (2-ME2), a promising anticancer agent, modulates Barrett's esophageal adenocarcinoma (BEAC) cell growth and behavior through cellular pathway involving beta-catenin in partnership with E-cadherin, which appears to play a critical role in the induction of antitumor responses in cancer cells. We found that 2-ME2 markedly reduced the BEAC cell proliferation via regulating apoptotic machinery such as Bcl-2 and Bax. It may nullify the aggressive behavior of the cells by reducing the migratory behavior. Expressions of beta-catenin and E-cadherin and binding of these two proteins is activated in a 2-ME2-dependent fashion in Bic-1 cells. Moreover, over expressions of these two proteins may be due to the stabilization of these proteins by 2-ME2. We found that 2-ME2-induced anti-migratory effects are mediated through the beta-catenin -E-cadherin signaling pathways. In view of these results, we determined whether 2-ME2 reduces BEAC tumor growth. Administration of 2-ME2 significantly decreased the growth of BEAC cells xenografted on the flank of nude mice. The evidence presented points out that the impact of 2-ME2 on beta-catenin-orchestrated signal transduction plausibly plays a multi-faceted functional role to inhibit the proliferation and cell migration of 2-ME2 treated malignant cells and it could be a potential candidate in novel treatment strategies for Barrett's esophageal adenocarcinoma

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 3712.
Abstract 3727: Phase 0 trials, obligation to research and ethical implications of health-care reform
Authors: Camporesi Silvia , Mameli Matteo
Published: February 2011

Biomedical knowledge is a public good; and people have a right to it. These two widely accepted assumptions are also at the core of the US Health Care reform. On the one hand, a public good needs the community's contribution in order to exist. On the other hand, people have also duties concerning public goods. Indeed, current patients rest on the shoulders of previous patients who contributed to the advancement of biomedical knowledge. Therefore, it can be argued that participation to research should be considered a “moral duty,” based on the arguments of free riding, reciprocity and fairness; and that default option should be to “opt in” to clinical trials.

While the debate revolving around a “obligation to research” dates back at least to the 1980s, it recently cropped up again, thanks to bioethicists John Harris and Ezekiel Emanuel (the latter, currently Special Advisor for Health Policy at the White House).

The 2006 FDA guidelines concerning first-in human clinical studies, also known as Phase 0 trials, are relevant to this discussion. Phase 0 studies aim to reduce the gap of translational research, and at speeding up the drug rate of approval. They are not suitable for all drug candidates, but only for those agents for which the molecular target and mechanism of effect are known. As they offer no therapeutic benefits to the participants, it has been argued that they pose an ethical dilemma. But a broader outlook on the ethical aspects needs to be taken here. Indeed, the existence of a scientific rationale for the design of study is a necessary, even if not sufficient, condition for its ethical justification; and it can be argued that the current framework of Phase 1 studies is not suitable for molecularly targeted agents, for which the maximum tolerate toxicity does not correlate with maximum efficacy.

Furthermore, if future trials will confirm the results of the first ABT-888 Phase 0 trial completed at NCI-NIH, and demonstrate that the risks of toxicity are negligible, it could be argued that Phase 0 trials represent the turning point for the envisaged cultural shift towards participation to research, as only in this context patients are offered the unique opportunity to contribute in a purely altruistic manner to the public good of biomedical knowledge. As a visiting PhD student at NCI-NIH sponsored by an UICC-ICRETT fellowship, I am currently developing a questionnaire to assess the comprehension of patients to Phase 0 clinical trials and their broader attitude towards participation to research. I will present my work 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 3727.
Abstract 3743: 18F-Fluorothymidine (18F-FLT) as tumor response predictor for anti-epidermal growth factor receptor antibody in human lung cancer xenograft
Authors: Takeuchi Satoshi , Zhao Songji , Kuge Yuji , Zhao Yan , Nishijima Ken-ichi , Hatano Toshiyuki , Shimizu Yasushi , Kinoshita Ichiro , Tamaki Nagara , Dosaka-Akita Hirotoshi
Published: February 2011

Background: Specific inhibition of epidermal growth factor receptor (EGFR) is one of the most promising treatment in the clinical setting. Cetuximab, a chimeric monoclonal antibody that binds to the extracellular domain of EGFR, has activity in colorectal cancer, non-small cell lung cancer, and so on. Because cetuximab is very expensive and has unique side effects, the development of appropriate evaluation for the therapeutic effects is necessary to use this drug effectively. Measurement of tumor proliferative activity by PET using 18F-Fluorothymidine (18F-FLT) may serve to assess early therapeutic effect. The purpose of this study is to determine whether 18F-FLT is useful to evaluate response to cetuximab treatment at a very early time-point in human lung cancer cell line xenograft.

Methods: Human tumor xenograft model was established in male BALB/c athymic mice by human lung cancer cell line NCI-H1975. These mice were assigned to two groups (n=5, each group): control and cetuximab-treated groups. Cetuximab was intra-peritoneally given 1.0 mg/body on the first day. 3H-FLT was given intravenously on day 3 and radioactivity in the tumor and other tissue samples (%Injected Dose/g/kg) was measured using liquid scintillation one hour later. Immunohistochemical labeling index (LI, %positive cells) staining of nuclear antigen Ki-67 was also studied in tumor tissues as a tumor cell proliferation marker.

Results: 3H-FLT uptake was higher in tumors compared with any other organs. The mean value of 3H-FLT uptake in tumor was significantly decreased to 55% of control value (0.38 ± 0.03 %ID/g/kg in control group vs. 0.21 ± 0.07 %ID/g/kg in cetuximab-treated group; p < 0.05). As compared with control, Ki-67 LI was significantly decreased in cetuximab-treated group (21.8 ± 6.7 %positive cells in control group vs. 2.2 ± 1.2 %positive cells in cetuximab-treated group; p < 0.001), while there was no significant changes in tumor volume and body weight between two groups.

Conclusions: In this animal model, 3H-FLT uptake and Ki-67 expression were decreased in cetuximab-treated group just two days after the treatment start. These results indicate 18F-FLT-PET can be a useful predictor to evaluate response to molecular targeted medicine such as cetuximab at a very early time-point of treatment before significant change of tumor size.

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 3743.
Abstract 3754: A prospective imaging biomarker trial for early identification of GBM patients resistant to first line therapy
Authors: Galban Craig J. , Chenevert Thomals L. , Meyer Charles R. , Tsien Christina , Lawrence Theodore S. , Hamstra Daniel A. , Junck Larry , Sundgren Pia C. , Johnson Timothy D. , Rehemtulla Alnawaz , Ross Brian D.
Published: February 2011

We assessed whether quantification of therapeutic-associated tumor cellularity and hemodynamic alterations may help in the early assessment of treatment resistance in patients with high grade glioma. Patients with high grade glioma (n=45) received concurrent chemoradiation. Apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) maps were acquired prior to chemoradiation and at week 3 during treatment on a prospective IRB-approved study. Clinical and conventional MR parameters, including average baseline ADC and rCBV and radiological response, were evaluated as prognostic indicators of one-year survival. Parametric response map (PRM), an innovative, voxel-by-voxel method of image analysis, was also performed. Of 45 patients, median survival was found to be 14.9 months with 44% of patients living shorter than one year (median survival of 6.6 months). Baseline ADC was the only single model not found to be predictive of survival at one year, whereas in a multivariate analysis PRMADC+ and PRMrCBV- had a stronger correlation to survival than baseline rCBV. Overall, a composite model of PRMADC+ and PRMrCBV- was found to have the strongest correlation with one-year survival. This study demonstrates the potential of a composite parametric model sensitive to both tumor cellularity and hemodynamic alterations following first line therapy for providing an early assessment of patient resistant to chemoradiation.

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 3754.
Abstract 3759: Discordance of the immunohistochemical expression of phospho-Akt and phosphor-ERK between paired biopsy and hepatectomy specimens of hepatocellular carcinoma
Authors: Shao Yu-Yun , Chen Chi-Long , Huang Chien-Chung , Tu Hui-Ching , Lin Zhong-Zhe , Hsu Chih-Hung , Cheng Ann-Lii
Published: February 2011

Background: Immunohistochemical (IHC) staining using archival tumor tissues is commonly used to study biomarkers of hepatocellular carcinoma (HCC). However, there are no biomarkers proven to be useful for personalized therapy of HCC so far. Since HCC is particularly susceptible to ischemia during and after the operation, the study sought to clarify the consistency of the IHC expression between biopsied and surgically resected HCC tissues.

Methods: HCC patients who had both biopsy and hepatectomy tumor tissues were enrolled. IHC staining was done with rabbit antibodies (Cell Signaling, Beverly, MA, US.) against p-Akt (Ser473) and p-ERK1/2 (Thr202/Tyr204). The staining and its evaluation were performed by a pathologist who was blinded to the identification of the slides. The expression levels of both proteins were graded according to the percentage of positively stained cells in every section, as follows: negative: 0%; 1+: 1-10%; 2+: 10-50%, and 3+: > 50%. Staining results of biopsy and hepatectomy tissues were compared.

Results: Forty-six tissue pairs were enrolled. The results of IHC staining were shown in the table. The expression was significantly decreased in hepatectomy tissues compared to biopsied tissue for both p-Akt and p-ERK (p < 0.001 and p < 0.001, respectively, by paired t test). The correlation of IHC staining results of paired tissues is poor. Spearman correlation coefficients for p-Akt (r = 0.116) and p-ERK (r = 0.112) were low. If using staining results as a continuous variable in analysis, the correlation between paired tissues remained poor, with Pearson correlation coefficients of 0.418 for p-Akt and 0.219 for p-ERK, respectively.

Conclusions: The consistency of p-Akt and p-ERK IHC staining between preoperative biopsy and hepatectomy HCC tissues is poor. This confounding factor should be taken into account in data for biomarkers of HCC. (The study was supported by the grant of NSC 98-3112-B-002-038.)IHC staining results of p-Akt and p-ERKMarkerTissue acquisition01+2+3+p-AktLiver tumor biopsy6.5%6.5%13.0%73.9% Hepatectomy tissue15.2%37.0%32.6%13.0%p-ERKLiver tumor biopsy2.2%10.9%23.9%60.9% Hepatectomy tissue8.7%63.0%17.4%6.5%

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 3759.
Abstract 3765: Prediction of pancreatic cancer growth based on multiple markers
Authors: Aoki-Kinoshita Kiyoko F. , Chen Xi , Ching Wai-Ki , Yokozawa Karin , Shimada Kazuaki , Hiraoka Nobuyoshi , Maeshiro Kensei , Furuta Koh
Published: February 2011

In the clinical laboratory, large amounts of laboratory data are accumulated, which may provide clues to aid in the prediction of various disease states. However, most work has focused on finding a single marker for diagnosis, which oftentimes perform poorly. The reason for this is that combinations of multiple markers are what need to be used for prediction, complicating matters. In the bioinformatics field, support vector machines (SVMs) for classification and feature extraction have gained much popularity due to their ability to handle multi-dimensional data and to pinpoint (combinations of) specific features that are key to the classification problem at hand. Using our preoperative clinical laboratory data based on 254 surgically operated and histologically confirmed pancreatic cancer patients, we attempted to classify the extent of cancer growth by (1) first finding the most pertinent markers, or features, for classification, (2) training the SVM classifier using the selected features, and (3) using the discrimination scores returned by the SVM to draw a line between the classes such that predictions can be made directly from the clinical laboratory data. We tested various classifications, such as between poorly- and well-differentiation of cancer growth, and as a result of (1), we found that previously suspected markers always ranked highly: CA19-9, elastase I, amylase, and fibrinogen. After performing step 2, we were able to establish an equation for each classification using the corresponding features such that new clinical laboratory data can be automatically classified as belonging to one of the trained classes. Thus, by specifying the values of CA19-9, elastase I and amylase for a new patient, for example, if the result of the equation is > 0, we may predict well differentiated cancer whereas a value of < 0 indicates poorly differentiated cancer. Using these equations, we could accurately classify our current data at a rate of almost 90% accuracy. Previous work have shown that SVMs are useful in prediction, but this is the first work that presents a mathematical model that can directly utilize clinical laboratory data for diagnosis, indicating its strong potential as an indicator for cancer growth prediction based on multiple markers.

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 3765.
Abstract 3767: Detection biomarkers for squamous cell bladder carcinoma in a global setting
Authors: Al-Delaimy Wael , Shokeir Ahmed
Published: February 2011

Bladder cancer is the fifth common malignancy in the US, and internationally it is the second most common cause of mortality from genitourinary malignancies after prostate cancer. Current clinical practice and recommendations do not include early screening for prevention. The use of cystoscopy cannot become a routine screening method of early detection due to limitations, including cost, while cytology is specific but not sensitive. Biomarkers that screen for bladder cancer before it becomes invasive are an alternative viable solution if validated and made cost-effective. Studies have mostly looked at translational cell bladder cancer and not squamous cell bladder cancer that is much more common in many parts of Africa, including Egypt and related to Schistomiasis parasitic infection. The aim in this study was to validate the use of three FDA approved biomarkers of early detection of translational baldder cancer on squamous bladder cancer in Egypt. The NMP22, Telomerase, and CD44 test kits were used for urine sample from 60 squamous bladder cancer patients and 60 non-cancer population controls. The cases and the controls were recruited from the Urology and Nephrology Center at Mansora University in Mansora, Egypt. Patients were diagnosed by cytoscopy and cytology. There was a significant difference in mean NMP22, CD44 and Telomerase levels among cases compared to controls. However, when adjusting for age and sex, only NMP22 and Telomerase remained significant. There was no significant difference among bladder cancer patients for presence or absence of a mass or schistomiases infection. CD44 and NMP22 mean levels were higher among patients if they were with stages 3 or 4 of bladder cancer compared to stages 1or 2 but this did not reach statistical significance. NMP22 and Telomerase biomarkers had better specificity and sensitivity than CD44 in predicting bladder cancer as shown by the Receiver Operating Characteristics (ROC) curves. In Conclusion, these biomarkers are satisfactory for detection of squamous cell bladder cancer, especially NMP22 and telomerase, and can become routinely used in the clinical setting in developing countries with high percentage of squamous cell bladder cancer. The next phase of biomarker validation for these assays among high-risk populations is warranted.

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 3767.
Abstract 377: Inhibition of c-Met and VEGFR by XL184 reduces tumor invasiveness and metastasis and prolongs survival of RIP-Tag2 transgenic mice
Authors: Sennino Barbara , Naylor Ryan M. , Tabruyn Sebastien P. , You Weon-Kyoo , Aftab Dana T. , McDonald Donald M.
Published: February 2011

Recent studies have shown that inhibition of VEGF signaling can promote tumor invasiveness and metastasis in some preclinical models. The mechanism underlying the increased aggressiveness is not fully understood but activation of the hepatocyte growth factor/c-Met pathway may be a factor. We addressed this mechanism by determining whether inhibition of VEGFR and c-Met together can reduce tumor growth and invasiveness and improve host survival. Our approach was to compare the effects of a tyrosine kinase inhibitor, XL184 (BMS-907351), which blocks VEGFR and c-Met, with the effects of an antibody that selectively blocks mouse VEGF. After treatment of pancreatic islet cell tumors in 14-week-old RIP-Tag2 mice withanti-mouse VEGF antibody for 3 weeks, the tumors were smaller (tumor area 4.3 ± 0.8 mm2 in antibody group versus 17.3 ± 6.5 mm2 in vehicle group, P < 0.05) but had greater expression of c-Met. Tumors treated with anti-VEGF antibody also had more irregular borders, indicative of invasion of the surrounding acinar pancreas (invasion index 18.9 versus 12.7 in vehicle group, P < 0.05), and more abundant liver metastases (metastases 2.73 ± 1.83 /mm2 versus 0.45 ± 0.12 /mm2 in vehicle group, P < 0.05). By comparison, mice treated with XL184 not only had smaller tumors (tumor area 0.7 ± 0.1 mm2, P < 0.05) than in the other groups but also had less invasive tumors (invasion index 4.5, P < 0.05), and lacked liver metastases. All mice treated with XL184 from 14 weeks of age survived until 20 weeks (n = 6), but none treated with vehicle (n = 14) or anti-VEGF antibody (n = 8) reached that end point. These results show that selective inactivation of VEGF reduces tumor growth but leads to greater invasiveness and metastasis in the RIP-Tag2 model. However, inhibition of VEGFR and c-Met by XL184 not only slows tumor growth but also decreases tumor invasiveness and liver metastasis and prolongs host survival.

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 377.
Abstract 3783: RRIG1 suppress growth and invasion of prostate cancer cell lines through inactivation of Src and RhoA
Authors: Hoque Ashraful , Chen Hongli , Guan Baoxiang , Xu Xiao-chun
Published: February 2011

In our previous studies, we have demonstrated that expression of retinoid receptor-induced gene 1 (RRIG1) was significantly reduced in different human cancers and that restoration of RRIG1 expression suppressed tumor cell growth in vitro and in vivo. In prostate cancer, we have showed that PC3 cells do not express RRIG1 but 22RV1 express high levels of RRIG1 mRNA. In this study, we first analyzed RRIG1 expression in prostate cancer tissue specimens and then transfected RRIG1 cDNA into PC3 cells and RRIG1 antisense cDNA into 22RV1 cells to restore or knockdown RRIG1 expression in these cells, respectively. We found that expression of RRIG1 protein was significantly downregulated in prostate cancer tissues compared to the normal tissues. Moreover, stably RRIG1-transfected prostate cancer cells grew much slower than that of the controls, whereas the antisense RRIG1-transfected 22RV1 cells grew faster than that of the controls. After that, we assessed the ability of migration and invasion of these stable cells using Boyden chamber assay and found that RRIG1 transfection reduced tumor cell migration and invasion in PC3 cells compared to the control transfections. In contrast, the antisense RRIG1 transfection promoted the tumor cell migration and invasion in 22RV1 cells. Molecularly, we found that RRIG1 was binding to Src protein and suppressed Src phosphorylation as well as RhoA activation. Consequently, RRIG1 reduced expression of phosphorylated Erk1/2 and AKT as well as expression of c-Jun, COX-2, and cyclinD1. The results from the current study demonstrated a tumor-suppressive effect of RRIG1 in prostate cancer, suggesting that RRIG1 gene may play a role in suppressing prostate tumorigenesis and progression.

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 3783.
Abstract 3797: Luteolin induces cytotoxicity in lung cancer cells depending on superoxide-mediated MKP-1 degradation and JNK activation
Authors: Bai Lang , Xu Shanling , Wang Xia , Ju Wei , Chen Wenjie , Lin Yong
Published: February 2011

Epidemiological studies have suggested luteolin (3′,4′,5,7-tetrahydroxyflavone) as a potential cancer preventive agent. Recently we found that luteolin selectively kills lung cancer but not immortalized human normal bronchial epithelial cells (HBECs). To elucidate the mechanism of luteolin's cancer cell killing activity, we investigated the cytotoxic cellular signaling pathway in lung cancer cells. The results show that luteolin potently induced both apoptosis and necrosis, which was associated with mitochondrion-dependent superoxide accumulation in lung cancer cells. The c-Jun N-terminal kinase (JNK) was substantially activated in luteolin treated cancer cells and luteolin-induced cytotoxicity was effectively blocked when JNK was inhibited. The reactive oxygen species scavengers BHA and NAC, which effectively block luteolin-induced superoxide accumulation, potently suppressed luteolin-induced JNK activation and cytotoxicity, suggesting that luteolin's lung cancer cell killing requires superoxide-mediated JNK activation. Furthermore, JNK activation was tightly associated with a superoxide-dependent rapid reduction of the JNK inactivating phosphatase MKP-1, which was mainly due to destabilizing MKP-1 protein. These results suggest that inhibiting MKP-1 is the main mechanism for luteolin-induced JNK activation. Thus, luteolin activates a novel cytotoxic pathway consisting of superoxide, MKP-1 and JNK in lung cancer cells. Interestingly, luteolin failed in inducing MKP-1 degradation and JNK activation and cell death in the HBECs, although superoxide induction by luteolin was comparable to that in lung cancer cells. Therefore, luteolin-induced cellular signaling in normal and lung cancer cells diverges at JNK activation. Taken together, our results suggest that activation of the speroxide/MKP1/JNK pathway underlies the main mechanism of luteolin's selective ctyotoxicity in lung cancer cells and manipulation of this pathway could be a useful approach for applying luteolin for lung cancer prevention and therapy.

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 3797.
Abstract 3803: 3,3-Diindolylmethane enhances Taxotere-induced apoptosis in breast cancer cells through FoXM1 downregulation
Authors: Rahman KM , Ahmad Aamir , Ali Shadan , Wang Zhiwei , Sethi Seema , Sakr Wael
Published: February 2011

Emerging evidence suggests that the transcription factor Forkhead Box M1 (FoxM1) is associated with the aggressive human carcinomas, including breast cancer. Since elevated expression of FoxM1 is observed in human breast cancers, FoxM1 has attracted growing attention as a potential target for the prevention or therapeutic intervention in breast cancer. However, no information is currently available regarding how down-regulation of FoxM1 could be achieved by any agents without toxicity, and whether this down-regulation could result in any benefit for patients diagnosed with breast cancer. 3,3′-diindolylmethane is a chemopreventive agent that has shown anti-tumor effects in various tumors. Currently there are no reports documenting the role of DIM in the inhibition of FoXM1, which will sensitize breast cancer cells to conventional therapeutic agents. Using a variety of breast cancer cells, we investigated the effect of DIM alone and in combination with Taxotere. Using multiple approaches such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, gene transfection, flow cytometry, real-time reverse transcription-PCR, Western blotting, migration, invasion, and angiogenesis assays, we found that DIM enhanced Taxotere-induced apoptotic cell death in breast cancer cells. These enhancing effect were related to the down-regulation of FoxM1, as well as the inhibition of cell growth, decrease in cell migration, and invasion of breast cancer cells. We also found that knockdown of FoXM1 expression by small interfering RNA transfection increased DIM-induced cell growth inhibition and apoptosis, whereas overexpression of FoxM1 by cDNA transfection minimized DIM-induced cell growth inhibition and apoptosis in breast cancer cells. Furthermore, combination treatment significantly inhibited tumor growth, and the results were correlated with the down-regulation of FoXM1. From these results, we conclude that inactivation of FoxM1 and its target genes by DIM enhanced the therapeutic efficacy of Taxotere in breast cancer, which could be useful for the treatment and/or prevention of aggressive 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 3803.
Abstract 3804: Transcriptional repression of androgen receptor in human prostate cancer cells by plant flavone apigenin
Authors: Shukla Sanjeev , Gupta Sanjay
Published: February 2011

Accumulating evidence suggest that androgen receptor (AR)-mediated signaling plays an important role in the development and progression of prostate cancer. Although Prostate Cancer Prevention Trial (PCPT) showed controversial results however manipulation of AR signaling pathway reduced the incidence of prostate cancer. Safer agents are needed that can modulate AR signaling pathways with effective suppression of prostate cancer. Plant flavonoids have been shown to possess weak oestrogenic and anti-androgen activity. Apigenin, a naturally occurring plant flavone, has shown promising anticancer activity by modulating several signaling pathways that have relevance to prostate cancer. However, the effect of apigenin on AR signaling has not been fully investigated. Using androgen-responsive human prostate cancer LNCaP and 22Rv1cells, we determine the effect of apigenin on androgen receptor signaling. Exposure of these cells with 5-40μM apigenin suppressed cell proliferation and arrested cells in sub G0-G1 phase of the cell cycle after 5nM dihydrotestosterone (DHT) stimulation. Apigenin inhibited endogenous prostate-specific antigen (PSA) transcription and reduced intracellular and secreted PSA protein levels induced by DHT in these cells. In LNCaP cells apigenin inhibited AR expression in a concentration-dependent manner by restricting its translocation into the nucleus. Co-transfection of PC-3 cells with wild-type AR-GFP-tag plasmid demonstrated that apigenin has ability to inhibit DHT-induced AR translocation into the nucleus. Additionally, receptor binding assays indicated that apigenin is a strong competitive inhibitor of DHT binding to the AR. These observations matched with the results of structural modeling studies exhibiting that apigenin is remarkably similar in conformational geometry and surface charge distribution to synthetic AR antagonist, flutamide, although the atomic compositions of the two substances were quite different. Taken together, our results indicate that apigenin exhibits potent anti-proliferative and anti-androgenic properties and may be developed as useful and safer agent for prevention/therapy of prostate 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 3804.
Abstract 3806: Stimulation of anti-leukemia immune response by a rice protein prolamin
Authors: Liao Hui-Fen , Chen Yu-Jen , Chen Yu-Yawn
Published: February 2011

Rice (Oryza sativa), an important cereal as a staple food worldwide, has been demonstrated that its water extracts benefit anti-leukaemia immunity. The present study isolated and characterized the active rice proteins and assessed the anti-leukemia response via in vitro and ex vivo experiments. Proteomic analysis identified various protein spots known with functions involving metabolism-related, transport, storage, antioxidation, development, and disease resistance proteins. Among these, storage proteins were the most abundant. To avoid masking the other relatively scanty rice storage proteins, albumin, globulin, glutelin and prolamin were separated and quantified. Prolamin-prepared conditioned medium of human mononuclear cells (MNC-CM) showed the greatest inhibition of human leukaemia U937 cell growth. Prolamin enhanced MNC to secrete tumor necrosis factor-α and prolamin-prepared MNC-CM induced U937 cells toward monocyte differentiation, not only by morphological observation, but also by NBT-reduction test. Neutralization of prolamin by polyclonal antibody attenuated its activity. Prolamin has greater activity than wheat gluten (glutenin and gliadin), which can cause celiac disease (CD). Additionally, rice proteins were undetectable by wheat gliadin-specific antibody, suggesting that rice may be an ideal candidate of food substitute in CD patients. In conclusion, rice prolamin is effective in activating human anti-leukaemia immunity and may not induce unwanted inflammatory diseases.

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 3806.
Abstract 383: Down-regulation of tumoral Hypoxia-Inducible Factor-1α expression in OVCAR-3 tumors by albendazole
Authors: Pourgholami Mohammad H. , Cai Zhao Yan , Badar Samina , Poruchynsky Marianne , Morris David Lawson
Published: February 2011

Purpose: To determine if albendazole (ABZ) interferes with the tumoral production of HIF-1α and VEGF proteins.

Procedures: Human ovarian cancer OVCAR-3 cells were exposed to hypoxic conditions and the affect of ABZ on HIF-1α and VEGF expression was determined. In vivo, female nude mice bearing intraperitoneal tumors were treated with an acute dose of ABZ (150 mg/kg, i.p.), and then euthanased at various time points (1, 6, 24, 48 and 72 h). Excised tumors were analysed for HIF-1α and VEGF expression.

Results: ABZ blocked the hypoxia-induced surge in HIF-1α protein. In mice, tumoral expression of HIF-1α and VEGF proteins were highly suppressed by ABZ in a reversible time-dependent manner. In drug treated mice, tumor VEGFmRNA levels were also profoundly suppressed.

Conclusion: The results show that the anti-VEGF effect is mediated through the inhibition of HIF-1α.

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 383.