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      1. Author :
        Hokaiwado, Naomi; Takeshita, Fumitaka; Naiki-Ito, Aya; Asamoto, Makoto; Ochiya, Takahiro; Shirai, Tomoyuki
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2008
      5. Publication :
        Carcinogenesis
      6. Products :
      7. Volume :
        29
      8. Issue :
        6
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Androgens; Animals; Animals, Genetically Modified; Apoptosis; Bioware; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Glutathione S-Transferase pi; Humans; In Situ Nick-End Labeling; Male; Neoplasm Transplantation; Oligonucleotide Array Sequence Analysis; PC-3M-luc; Prostatic Neoplasms; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering
      12. Abstract :
        Prostate cancers generally acquire an androgen-independent growth capacity with progression, resulting in resistance to antiandrogen therapy. Therefore, identification of the genes regulated through this process may be important for understanding the mechanisms of prostate carcinogenesis. We here utilized androgen-dependent/independent transplantable tumors, newly established with the 'transgenic rat adenocarcinoma in prostate' (TRAP) model, to analyze their gene expression using microarrays. Among the overexpressed genes in androgen-independent prostate cancers compared with the androgen-dependent tumors, glutathione S-transferase pi (GST-pi) was included. In line with this, human prostate cancer cell lines PC3 and DU145 (androgen independent) had higher expression of GST-pi compared with LNCaP (androgen dependent) as determined by semiquantitative reverse transcription-polymerase chain reaction analysis. To investigate the roles of GST-pi expression in androgen-independent human prostate cancers, GST-pi was knocked down by a small interfering RNA (siRNA), resulting in significant decrease of the proliferation rate in the androgen-independent PC3 cell line. In vivo, administration of GST-pi siRNA-atelocollagen complex decreased GST-pi protein expression, resulting in enhanced numbers of TdT mediated dUTP-biotin nick-end labering (TUNEL)-positive apoptotic cells. These findings suggest that GST-pi might play important roles in proliferation of androgen-independent human prostate cancer cells.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/18413363
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8967
      1. Author :
        Kuo, Chaincy; Coquoz, Olivier; Troy, Tamara L; Xu, Heng; Rice, Brad W
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2007
      5. Publication :
        Journal of biomedical optics
      6. Products :
      7. Volume :
        12
      8. Issue :
        2
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Bioware; Image Interpretation, Computer-Assisted; Imaging, Three-Dimensional; Luminescent Proteins; Male; Mice; Microscopy, Fluorescence, Multiphoton; PC-3M-luc; Prostatic Neoplasms; Whole Body Imaging
      12. Abstract :
        A new method is described for obtaining a 3-D reconstruction of a bioluminescent light source distribution inside a living animal subject, from multispectral images of the surface light emission acquired on charge-coupled device (CCD) camera. The method uses the 3-D surface topography of the animal, which is obtained from a structured light illumination technique. The forward model of photon transport is based on the diffusion approximation in homogeneous tissue with a local planar boundary approximation for each mesh element, allowing rapid calculation of the forward Green's function kernel. Absorption and scattering properties of tissue are measured a priori as input to the algorithm. By using multispectral images, 3-D reconstructions of luminescent sources can be derived from images acquired from only a single view. As a demonstration, the reconstruction technique is applied to determine the location and brightness of a source embedded in a homogeneous phantom subject in the shape of a mouse. The technique is then evaluated with real mouse models in which calibrated sources are implanted at known locations within living tissue. Finally, reconstructions are demonstrated in a PC3M-luc (prostate tumor line) metastatic tumor model in nude mice.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/17477722
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8968
      1. Author :
        Giubellino, Alessio; Gao, Yang; Lee, Sunmin; Lee, Min-Jung; Vasselli, James R; Medepalli, Sampath; Trepel, Jane B; Burke, Terrence R, Jr; Bottaro, Donald P
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2007
      5. Publication :
        Cancer research
      6. Products :
      7. Volume :
        67
      8. Issue :
        13
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Bioware; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; GRB2 Adaptor Protein; Humans; Mice; Mice, SCID; Microscopy, Fluorescence; Neoplasm Metastasis; Neoplasm Transplantation; PC-3M-luc; Protein Binding; Protein Structure, Tertiary; Tetrazolium Salts; Thiazoles
      12. Abstract :
        Metastasis, the primary cause of death in most forms of cancer, is a multistep process whereby cells from the primary tumor spread systemically and colonize distant new sites. Blocking critical steps in this process could potentially inhibit tumor metastasis and dramatically improve cancer survival rates; however, our understanding of metastasis at the molecular level is still rudimentary. Growth factor receptor binding protein 2 (Grb2) is a widely expressed adapter protein with roles in epithelial cell growth and morphogenesis, as well as angiogenesis, making it a logical target for anticancer drug development. We have previously shown that a potent antagonist of Grb2 Src homology-2 domain-binding, C90, blocks growth factor-driven cell motility in vitro and angiogenesis in vivo. We now report that C90 inhibits metastasis in vivo in two aggressive tumor models, without affecting primary tumor growth rate. These results support the potential efficacy of this compound in reducing the metastatic spread of primary solid tumors and establish a critical role for Grb2 Src homology-2 domain-mediated interactions in this process.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/17616655
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8969
      1. Author :
        Figg, William D; Li, Haiqing; Sissung, Tristan; Retter, Avi; Wu, Shenhong; Gulley, James L; Arlen, Phil; Wright, John J; Parnes, Howard; Fedenko, Kathy; Latham, Lea; Steinberg, Seth M; Jones, Elizabeth; Chen, Clara; Dahut, William
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2007
      5. Publication :
        BJU international
      6. Products :
      7. Volume :
        99
      8. Issue :
        5
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Aged; Androgens; Animals; Antineoplastic Combined Chemotherapy Protocols; Aryl Hydrocarbon Hydroxylases; Bioware; Cytochrome P-450 Enzyme System; Estramustine; Genotype; Humans; Male; Mice; Mice, Nude; Middle Aged; PC-3M-luc; Prostatic Neoplasms; Survival Analysis; Taxoids; Thalidomide; Treatment Outcome
      12. Abstract :
        OBJECTIVE To evaluate the combination of docetaxel plus estramustine (which prolongs survival in patients with androgen-independent prostate cancer, AIPC), and thalidomide (that also adds to docetaxel activity), both pre-clinically and clinically in AIPC. PATIENTS, MATERIALS AND METHODS In the pre-clinical evaluation we injected PC3 cells subcutaneously into severely combined immunodeficient mice and started treatment after the tumour volume reached 50 mm3. We also evaluated the combination using luciferase-labelled PC3M-luc-C6 cells in nude mice. We enrolled 20 patients with metastatic progressive AIPC into a phase II clinical trial to evaluate this combination. Docetaxel (30 mg/m2) was administered every week, for 3 of 4 weeks. The dose of thalidomide was 200 mg/day and estramustine was given three times a day at 1, 2, 3, 8, 9, 10, 15, 16 and 17 days. RESULTS In the mice, thalidomide with docetaxel plus estramustine reduced tumour volume by 88% at 17 days vs the control treatment (p=0.001). The combination of docetaxel, estramustine and thalidomide nearly eradicated the signal from the luciferase-expressing PC3M cells in the metastasis model. Clinically, the progression-free time was 7.2 months with this combination; 18 of 20 patients had a decline of half or more in prostate-specific antigen level and two of 10 patients with soft-tissue lesions had a partial response on computed tomography. There were 24 grade 3 and two grade 4 complications associated with this combination. There was a statistically significant association between overall survival and the CYP1B1*3 genotype (P=0.013). CONCLUSION Docetaxel-based chemotherapy is now regarded as a standard regimen for metastatic AIPC. The combination of estramustine, docetaxel and thalidomide is an advantageous treatment in pre-clinical models of prostate cancer and is a safe, tolerable and active regimen in patients with AIPC.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/17437439
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8970
      1. Author :
        Casarez, Eli V; Dunlap-Brown, Marya E; Conaway, Mark R; Amorino, George P
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2007
      5. Publication :
        Cancer research
      6. Products :
      7. Volume :
        67
      8. Issue :
        17
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Bioware; Carcinoma; Estradiol; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; PC-3M-luc; Phosphorylation; Prostatic Neoplasms; Radiation-Sensitizing Agents; Subcutaneous Tissue; Transplantation, Heterotopic; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
      12. Abstract :
        2-Methoxyestradiol (2ME2) is an endogenous estradiol metabolite that inhibits microtubule polymerization, tumor growth, and angiogenesis. Because prostate cancer is often treated with radiotherapy, and 2ME2 has shown efficacy as a single agent against human prostate carcinoma, we evaluated 2ME2 as a potential radiosensitizer in prostate cancer models. A dose-dependent decrease in mitogen-activated protein kinase phosphorylation was observed in human PC3 prostate cancer cells treated with 2ME2 for 18 h. This decrease correlated with in vitro radiosensitization measured by clonogenic assays, and these effects were blocked by the expression of constitutively active MEK. Male nude mice with subcutaneous PC3 xenografts in the hind leg were treated with 2ME2 (75 mg/kg) p.o. for 5 days, and 2 Gy radiation fractions were delivered each day at 4 h after drug treatment. A statistically significant super-additive effect between radiation and 2ME2 was observed in this subcutaneous model, using analysis of within-animal slopes. A PC-3M orthotopic model was also used, with bioluminescence imaging as an end point. PC-3M cells stably expressing the luciferase gene were surgically implanted into the prostates of male nude mice. Mice were given oral doses of 2ME2 (75 mg/kg), with radiation fractions (3 Gy) delivered 4 h later. Mice were then imaged weekly for 4 to 5 weeks with a Xenogen system. A significant super-additive effect was also observed in the orthotopic model. These data show that 2ME2 is an effective radiosensitizing agent against human prostate cancer xenografts, and that the mechanism may involve a decrease in mitogen-activated protein kinase phosphorylation by 2ME2.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/17804747
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8972
      1. Author :
        Beckers, Annelies; Organe, Sophie; Timmermans, Leen; Scheys, Katryn; Peeters, Annelies; Brusselmans, Koen; Verhoeven, Guido; Swinnen, Johannes V
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2007
      5. Publication :
        Cancer research
      6. Products :
      7. Volume :
        67
      8. Issue :
        17
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Acetyl-CoA Carboxylase; Apoptosis; Autophagy; Bioware; Cell Death; Cell Proliferation; Drug Evaluation, Preclinical; Fatty Acids; Humans; Macrolides; Male; Neoplasms; Palmitic Acid; PC-3M-luc; Phospholipids; Prostatic Neoplasms; Tumor Cells, Cultured
      12. Abstract :
        Development and progression of cancer is accompanied by marked changes in the expression and activity of enzymes involved in the cellular homeostasis of fatty acids. One class of enzymes that play a particularly important role in this process are the acetyl-CoA carboxylases (ACC). ACCs produce malonyl-CoA, an intermediate metabolite that functions as substrate for fatty acid synthesis and as negative regulator of fatty acid oxidation. Here, using the potent ACC inhibitor soraphen A, a macrocyclic polyketide from myxobacteria, we show that ACC activity in cancer cells is essential for proliferation and survival. Even at nanomolar concentrations, soraphen A can block fatty acid synthesis and stimulate fatty acid oxidation in LNCaP and PC-3M prostate cancer cells. As a result, the phospholipid content of cancer cells decreased, and cells stopped proliferating and ultimately died. LNCaP cells predominantly died through apoptosis, whereas PC-3M cells showed signs of autophagy. Supplementation of the culture medium with exogenous palmitic acid completely abolished the effects of soraphen A and rescued the cells from cell death. Interestingly, when added to cultures of premalignant BPH-1 cells, soraphen A only slightly affected cell proliferation and did not induce cell death. Together, these findings indicate that cancer cells have become dependent on ACC activity to provide the cell with a sufficient supply of fatty acids to permit proliferation and survival, introducing the concept of using small-molecule ACC inhibitors as therapeutic agents for cancer.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/17804731
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8974
      1. Author :
        Lyons, Scott K; Lim, Ed; Clermont, Anne O; Dusich, Joan; Zhu, Lingyun; Campbell, Kenneth D; Coffee, Richard J; Grass, David S; Hunter, John; Purchio, Tony; Jenkins, Darlene
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2006
      5. Publication :
        Cancer research
      6. Products :
      7. Volume :
        66
      8. Issue :
        9
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Androgens; Animals; Bioware; Cell Transformation, Neoplastic; Disease Models, Animal; Genes, Reporter; Humans; Image Processing, Computer-Assisted; In Situ Hybridization; Luciferases, Firefly; Luminescent Measurements; Male; Mice; Mice, Transgenic; PC-3M-luc; Promoter Regions, Genetic; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms
      12. Abstract :
        Several transgenic mouse models of prostate cancer have been developed recently that are able to recapitulate many key biological features of the human condition. It would, therefore, be desirable to employ these models to test the efficacy of new therapeutics before clinical trial; however, the variable onset and non-visible nature of prostate tumor development limit their use for such applications. We now report the generation of a transgenic reporter mouse that should obviate these limitations by enabling noninvasive in vivo bioluminescence imaging of normal and spontaneously transformed prostate tissue in the mouse. We used an 11-kb fragment of the human prostate-specific antigen (PSA) promoter to achieve specific and robust expression of firefly luciferase in the prostate glands of transgenic mice. Ex vivo bioluminescence imaging and in situ hybridization analysis confirmed that luciferase expression was restricted to the epithelium in all four lobes of the prostate. We also show that PSA-Luc mice exhibit decreased but readily detectable levels of in vivo bioluminescence over extended time periods following androgen ablation. These results suggest that this reporter should enable in vivo imaging of both androgen-dependent and androgen-independent prostate tumor models. As proof-of-principle, we show that we could noninvasively image SV40 T antigen-induced prostate tumorigenesis in mice with PSA-Luc. Furthermore, we show that our noninvasive imaging strategy can be successfully used to image tumor response to androgen ablation in transgenic mice and, as a result, that we can rapidly identify individual animals capable of sustaining tumor growth in the absence of androgen.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/16651422
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8975
      1. Author :
        Hanai, Koji; Takeshita, Fumitaka; Honma, Kimi; Nagahara, Shunji; Maeda, Miho; Minakuchi, Yoshiko; Sano, Akihiko; Ochiya, Takahiro
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2006
      5. Publication :
        Annals of the New York Academy of Sciences
      6. Products :
      7. Volume :
        1082
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Bioware; Bone Neoplasms; Collagen; Dermatitis; Disease Models, Animal; Drug Carriers; Gene Therapy; Humans; Hypersensitivity; Mice; Mice, Nude; Nanoparticles; Neoplasm Metastasis; Oligonucleotides; PC-3M-luc; RNA, Small Interfering; Tissue Distribution
      12. Abstract :
        The goal of our research is to provide a practical platform for drug delivery in oligonucleotide therapy. We report here the efficacy of an atelocollagen-mediated oligonucleotide delivery system applied to systemic siRNA and antisense oligonucleotide treatments in animal disease models. Atelocollagen and oligonucleotides formed a complex of nanosized particles, which was highly stable against nucleases. The complex allowed oligonucleotides to be delivered efficiently into several organs and tissues via intravenous administration. In a tumor metastasis model, the complex successfully delivered siRNA to metastasized tumors in bone tissue and inhibited their growth. We also demonstrated that a single intravenous treatment of the antisense oligodeoxynucleotide complex suppressed ear dermatitis in a contact hypersensitivity model. These results indicate the strong potential of the atelocollagen-mediated drug delivery system for practical therapeutic technology.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/17145919
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8976
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