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  • 1
    Electronic Resource
    Electronic Resource
    Osteocalcin-directed gene therapy for prostate-cancer bone metastasis (2000)
    Springer
    World journal of urology 18 (2000), S. 102-110 
    Details
    ISSN: 1433-8726
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Osteocalcin (OC) is a major noncollagenous bone protein whose expression is limited almost exclusively to osteotropic tumors and mature calcified tissue (differentiated osteoblasts). The function of OC, a highly conserved gamma-carboxyglutamic acid-containing protein, relies in part on its ability to bind hydroxyapatite and act as a chemoattractant for bone-resorbing cells. Serum osteocalcin levels are used clinically as an index of active bone turnover. Research in our laboratory has revealed that OC is expressed in several solid tumors, including osteosarcoma and ovarian, lung, brain, and prostate cancers. Evidence arising from reverse-transcription polymerase chain reaction (RT-PCR; detection of OC mRNA), immunohistochemical staining (detection of OC protein), and transient transfection and reporter assay (detection of OC mRNA transcription) reveals that OC expression is up-regulated in numerous solid tumors, with its expression being further elevated in androgen-independent prostate cancers. A recombinant, replication-defective adenovirus, Ad-OC-TK (OC promoter-driven herpes-simplex-virus thymidine kinase) was constructed and, when combined with the appropriate prodrug, either ganciclovir (GCV) or acyclovir (ACV), was found to be effective at destroying prostate-cancer cell lines in vitro and prostate tumor xenografts in vivo in both subcutaneous and bone sites. Additionally, via use of the OC promoter the supporting bone stromal cells are cotargeted when the prostate cancer interdigitates with bone stroma at the metastatic skeletal sites. Thus, maximal tissue-specific cell toxicity is achieved by the interruption of cellular communication between the prostate cancer and the bone stroma. We describe herein the preclinical foundation as well as the design and implementation of an ongoing phase I clinical trial at the University of Virginia that targets androgen-independent metastatic prostate cancer using the Ad-OC-TK vector.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s003450050181
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  • 2
    Electronic Resource
    Electronic Resource
    Targeting of cancer cells with monoclonal antibodies specific for C3b(i) (2000)
    Springer
    Cancer immunology immunotherapy 49 (2000), S. 551-562 
    Details
    ISSN: 1432-0851
    Keywords: Key words Complement ; Tumor antigen ; Monoclonal antibody ; Prostate cancer ; Purging
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: The goal of this research is to determine the feasibility of an immunotherapeutic approach based on the use of monoclonal antibodies (mAb) to target complement activation fragments on opsonized cancer cells. Methods: We investigated whether treatment of LNCaP and C4-2 human prostate cancer cell lines with normal human serum would allow for deposition of sufficient amounts of the complement-activation protein C3b and its fragments [collectively referred to as C3b(i)] such that these proteins could serve as cancer-cell-associated antigens for targeting by mAb. Radioimmunoassays, flow cytometry, and magnetic purging with specific immunomagnetic beads were used for the analyses. Results: In vitro opsonization of human prostate cancer cells with normal human serum resulted in deposition of C3b(i) in sufficient quantity (approx. 100,000 molecules/cell) for the cells to be targeted in a variety of protocols. We found that 51Cr-labeled and C3b(i)-opsonized cancer cells could be specifically purged at high efficiency (95%–99%) using anti-C3b(i) mAb covalently coupled to magnetic beads. Flow-cytometry experiments indicated that most normal white cells were not removed under similar conditions. Opsonization of cancer cells with sera from men with prostate cancer led to lower levels of cell-associated IgM and, subsequently, lower amounts of C3b(i) deposited than in normal subjects. Prototype experiments suggested that this deficiency could be corrected by addition of IgM from normal donor plasma. Conclusion: mAb directed against complement-activation products may provide new opportunities to deliver diagnostic and therapeutic agents selectively to cancer cells and tumor deposits. These opportunities may include ex vivo purging of C3b(i)-opsonized cancer cells prior to autologous bone marrow or stem cell transplantation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002620000140
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  • 3
    Electronic Resource
    Electronic Resource
    Human prostate cancer model: Roles of growth factors and extracellular matrices (1992)
    New York, N.Y. : Wiley-Blackwell
    Journal of Cellular Biochemistry 50 (1992), S. 99-105 
    Details
    ISSN: 0730-2312
    Keywords: extracellular matrices (ECMs) ; bFGF ; NGF ; HGF and KGF ; growth factors (GFs) ; human prostate cancer model ; prostate cancer-bone interaction ; stromal-epithelial interaction ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: A human prostate cancer model was established by inoculating a prostate specific antigen (PSA)-producing LNCaP cell line with either prostate or bone fibroblasts. Alternatively, this human prostate cancer model can also be established by inoculating LNCaP cell with growth factor(s) (GFs) and extracellular matrix (ECM) immobilized on Gelfoam®. The resulting LNCaP tumors were used to evaluate PSA production and excretion athymic hosts. This model was also employed to examine the biochemical nature of mesenchymal cell-derived growth-promoting protein(s) and to assess the efficacy of potential chemotherapeutic agents. Because of the propensity of human prostate cancer to metastasize to the bone, this study defined a 1.0 M NaCI-eluted fraction, MS1, from the conditioned medium of a bone stromal cell line (MS) by heparin-affinity column chromatography. The growth-promoting activity was assayed both in vivo (e.g., tumor formation) and in vitro (e.g., soft agar colony formation). We found that the growth-promoting activity was trypsin-and heat-sensitive, and partially degraded by acid and dithiothreitol. Immunochemical studies indicated that the polyclonal antibody raised against MS1 blocked the growth-promoting effect elicited by the bone-conditioned media. This growth-promoting factor was found to be immunochemically dissimilar to KGF, HGF, and bFGF. However, addition of bFGF, HGF and NGF, but not a FGF, TGFβ, IGF1, IGF2, PDGF, EGF, TGFα and KGF, stimulated anchorage-independent growth of prostate cells, a condition closely parallel to tumor formation in vivo. We found that the MS1 fraction also contained fibronectin and tenascin but not laminin or collagen IV. None of the ECM proteins induced soft agar colony formation by normal prostate epithelial cells. Therefore, it is possible that the ECM protein(s) may potentiate the tumor-inducing activity of locally produced GFs. © 1992 Wiley-Liss, Inc.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jcb.240501222
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  • 4
    Electronic Resource
    Electronic Resource
    Development of human prostate cancer models for chemoprevention and experimental therapeutics studies (1997)
    New York, N.Y. : Wiley-Blackwell
    Journal of Cellular Biochemistry 67 (1997), S. 174-181 
    Details
    ISSN: 0730-2312
    Keywords: prostate cancer progression ; stromal-epithelial interaction ; three-dimensional growth models ; prostate cancer bone metastasis ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: The progression of human prostate cancer from histomorphologic to clinical expression often requires several decades. This study emphasizes the importance of developing relevant human prostate cancer models to study the molecular events leading to prostate cancer progression. These models will provide a rational basis for chemopreventive and treatment strategies to retard the progression of human prostate cancer from its localized to its metastatic state. In our laboratory, we have established the LNCaP progression and ARCaP models and the in vitro three-dimensional growth models involving prostate cancer and bone stroma to study the progression of prostate cancer. We propose that prostate cancer may progress from an androgen-dependent to an androgen-independent state. While existing as androgen-independent tumors (defined as tumors capable of growing in castrated hosts and secreting PSA in serum), prostate cancer may assume three different phenotypes as it progresses: androgen-independent while remaining androgen-responsive; androgen-independent and unresponsive to androgen stimulation; and androgen-independent but suppressed by androgen. It is conceivable that any androgen-independent human prostate cancer may contain variable proportions of cells that exhibit these three phenotypes. This concept may have important implications in determining strategies for chemopreventive and therapeutic trials. We have established three-dimensional growth models of prostate cancer cells either in collagen gel or microgravity-simulated growth conditions to form viable and functional organoids which contain prostate cancer epithelial cells admixed with prostate or bone stromal cells. These in vitro models combined with the in vivo models described above will enhance our understanding of the regulatory mechanism of prostate cancer growth and progression, and hence could improve efficiency in screening chemopreventive and therapeutic agents which alter the biologic behaviors of human prostate cancer. J. Cell. Biochem. Suppls. 28/29:174-181. © 1998 Wiley-Liss, Inc.
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Interracial comparative study of prostate cancer in the United States, China, and Japan (1997)
    New York, N.Y. : Wiley-Blackwell
    Journal of Cellular Biochemistry 67 (1997), S. 182-186 
    Details
    ISSN: 0730-2312
    Keywords: prostate cancer in Chinese men ; angiogenesis ; neuroendocrine factors ; p53 protein ; ras oncogene ; androgen receptor ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: The interracial differences of prostate cancer progression have long been documented; however, underlying molecular and cellular mechanisms remain obscure. This study focuses on the histopathologic, immunohistochemical, biochemical, and molecular characterization of prostate cancer tissues unselectively obtained from US, Chinese, and Japanese men. Histopathologic analyses indicate that 74.5% of the prostate cancers in Chinese patients were poorly differentiated, compared with 28.6 and 32.8% of the prostate cancers in US and Japanese men, respectively. These differences cannot be attributed to patient age, clinical stage of disease, or methods of tissue sampling. Furthermore, the high proportion of poorly differentiated prostate cancer tissues in the Chinese group was not related to the patients' access to medical service or their geographic origins within China. We found significantly higher levels of tumor angiogenesis (2- to 4-fold), serotonin (2- to 20-fold), and bombesin (7- to 16-fold), but not chromogranin A, in tissue specimens obtained from Chinese prostate cancer patients compared with those from US and Japanese patients. We also found marked differences in p53 protein accumulation among various ethnic groups. The p53 protein was frequently detected in prostate cancer tissue specimens from Chinese (90.2%), but less frequently in US black (3.7%), US white (17.4%), and Japanese (7.1%) men. Further analysis of 31 prostate cancer tissues from Chinese men indicated that mutational changes in the p53 gene occurred between exons 5 and 8. J. Cell. Biochem. Suppls. 28/29:182-186. © 1998 Wiley-Liss, Inc.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
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