Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.2.1.23 (beta-galactosidase)
14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor suppressor gene p16 is a cyclin-dependent kinase inhibitor and an important negative cell cycle regulator. The inactivation of p16 appears to be a common event in prostate cancer. Replacement of p16 inhibits prostate tumor cell growth, but the mechanism is not known. Human prostate cancer cell lines PPC-1, which has an inactivated p16, and DU145, which has a nonfunctional retinoblastoma Rb protein (pRb), were used to determine the possible mechanism of p16 mediated growth inhibition. PPC-1 cells treated with 5-aza-2'-deoxycytidine (5-aza-dC), a demethylating agent, induced p16 expression, inhibited cell growth, and induced senescence. Similarly, PPC-1 cells transduced by an adenoviral vector containing the p16 gene (AdRSVp16) produced a p16 protein that suppressed cellular proliferation and induced senescence. Co-staining of AdRSVp16-transduced PPC-1 cells by p16 immunohistochemistry and by beta-galactosidase substrate X-gal showed that the morphologically enlarged cells expressed both p16 and senescence-associated beta-galactosidase. In contrast, AdRSVp16 did not induce senescence in DU145 cells, but did inhibit its growth. However, when wild-type pRb was introduced in DU145 cells, AdRSVp16 was able to induce senescence. Thus, the mechanism by which p16 suppressed prostate cancer was dependent on the pRb functional status of cells whereby p16 caused pRb+ cells to undergo inhibition by senescence, whereas pRb- cells were also inhibited, but not by senescence.
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PMID:p16/MTS1/INK4A suppresses prostate cancer by both pRb dependent and independent pathways. 1071 71

One potential use for prostate-cancer-associated genes discovered through ongoing genetics studies entails the construction of virus- or plasmid-based recombinant vector vaccines encoding these new tumor-associated antigens (TAA) to induce TAA-specific immune responses for the prevention or therapy of prostate cancer. Clinical trials evaluating prototypes of such recombinant vaccines are under way. TAA-encoding recombinant vector vaccines, however, have not previously been evaluated in a prostate-cancer animal model. For assessment of the potential susceptibility of prostate cancer to genetic immunization strategies using TAA-encoding recombinant vectors, the antitumor efficacy of a model recombinant viral vector encoding a TAA was evaluated in rat Dunning prostate cancer. Recombinant vaccinia was chosen as a prototype virus vector encoding a TAA for these studies, and beta-galactosidase was chosen as a model target TAA. Dunning AT-2 cells were transduced with a retroviral vector to express beta-galactosidase, and the susceptibility of tumorigenic AT-2-lacZ cells to immunization with vaccinia-lacZ was measured using protection studies in Copenhagen and nu/nu rats. Stably transduced AT-2-lacZ cells expressing beta-galactosidase as measured by enzymatic substrate-based assays were found to retain their tumorigenicity in vivo despite abundant expression of rat major histocompatibility complex (MHC) class I. Immunization with model TAA-encoding recombinant vaccinia-lacZ conferred significant protection against subsequent growth of AT-2-lacZ cells in vivo (P = 0.01); however, the efficacy of such immunization was markedly dependent on the volume of tumor challenge. The antitumor efficacy of TAA-encoding recombinant vaccinia immunization was abrogated in nu/nu rats, suggesting a T-cell-dependent mechanism of activity. These studies suggest that prostate cancer may be a suitable target for immunization strategies using TAA-encoding recombinant vectors. Such immunization strategies may be more effective in settings of minimal cancer burden.
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PMID:Antitumor efficacy of tumor-antigen-encoding recombinant poxvirus immunization in Dunning rat prostate cancer: implications for clinical genetic vaccine development. 1085 49

Treatment failure after radiation therapy of prostate cancer (PC) could be a significant problem. Our objective is to design genetic radiosensitizing strategies for the treatment of PC. Cells from individuals with the genetic disorder ataxia telangiectasia (AT) are hypersensitive to ionizing radiation. Therefore, we examined whether attenuation of the AT gene product, AT mutated (ATM), in PC cells could result in an increased intrinsic radiosensitivity. A p53-mutant PC cell line, PC-3 was infected with adenoviral vectors, expressing antisense ATM RNA to various domains of the ATM gene. Immunoblot analyses of cellular extracts from antisense ATM-transfected PC-3 cells showed attenuated expression of the ATM protein within 2 days of viral infection. Compared with cells infected with an adeno-beta-galactosidase vector, antisense ATM-transfected PC-3 cells showed aberrant control of S-phase cell-cycle checkpoints after exposure to ionizing radiation. Under these conditions, the intrinsic radiosensitivity of the PC-3 cells was enhanced. Consequently antisense ATM gene therapy could serve as a paradigm for strategies that target the cellular survival mechanisms of an irradiated tumor cell and may provide therapeutic benefit to patients undergoing radiation therapy for PC.
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PMID:Adenovirus-mediated antisense ATM gene transfer sensitizes prostate cancer cells to radiation. 1105 87

The purpose of this study was to determine the effects of interferon-beta (IFN-beta) gene transfer on the growth of PC3MM2 human prostate cancer cells in nude mice. Intralesional delivery of an adenoviral vector encoding murine IFN-beta (AdIFN-beta), but not a vector encoding bacterial beta-galactosidase (AdLacZ), suppressed PC3MM2 tumors in a dose-dependent manner. At the highest dose (2x10(9) plaque-forming units, PFU), a single injection of AdIFN-beta (but not AdLacZ) suppressed orthotopic PC3MM2 tumors and development of metastasis by 80%, and eradicated the tumors in 20% of mice. Immunohistochemical staining showed that AdIFN-beta-treated tumors contained fewer microvessels, fewer proliferating cells, and more apoptotic cells than did the control tumors. Compared with controls, tumors injected with AdIFN-beta expressed higher levels of IFN-beta and inducible nitric oxide synthase (iNOS) and lower levels of basic fibroblast growth factor (bFGF) and transforming growth factor beta1 (TGF-beta1). In vitro analysis indicated that expression of bFGF and TGF-beta1 in PC3MM2 cells could be suppressed by the nitric oxide donor sodium nitroprusside. These data suggest that intratumoral delivery of the IFN-beta gene with adenoviral vectors could be an effective therapy for prostate cancer and that tumor suppression by AdIFN-beta correlated with up-regulation of iNOS and down-regulation of angiogenesis.
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PMID:Adenovirus-mediated interferon-beta gene therapy suppresses growth and metastasis of human prostate cancer in nude mice. 1149 71

Prostate-specific antigen (PSA) is expressed by prostate epithelial cells and has a highly restricted tissue distribution. Prostatic malignancies in 95% of patients continue to express PSA, making this antigen a good candidate for targeted immunotherapy. The goals of our studies are to generate a recombinant PSA adenovirus type 5 (Ad5-PSA) that is safe and effectively activates a PSA-specific T-cell response capable of eliminating prostate cancer cells, and to characterize the immunologic basis for this rejection. Here we show that immunization of mice with Ad5-PSA induced PSA-specific cellular and humoral immunity that was protective against a subcutaneous challenge with RM11 prostate cancer cells expressing PSA (RM11psa), but not mock-transfected RM11 tumor cells (RM11neo). Mice immunized with recombinant adenovirus type 5 encoding beta-galactosidase (Ad5-lacZ) did not generate protective immunity. Antitumor activity was predominantly mediated by CD8(+) T lymphocytes. Although Ad5-PSA immunization prior to RM11psa challenge was protective, Ad5-PSA immunization alone was not able to control the growth of existing RM11psa tumors. In contrast, established RM11psa tumors ranging in size from 500 to 1,000 mm(3) were efficiently eliminated if Ad5-PSA priming was followed 7 days later by intratumoral injection of recombinant canarypox viruses (ALVAC) encoding interleukin-12 (IL-12), IL-2, and tumor necrosis factor-alpha. In this case, antitumor immunity was still dominated by CD8(+) T lymphocytes, but natural killer cells became necessary for a maximal response. These data provide information on the effector cell populations in a protective immune response to prostate cancer and demonstrate the utility of an Ad5-PSA vaccine combined with cytokine gene delivery to eliminate large established tumors that are refractory to other interventional methods.
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PMID:Immunization with type 5 adenovirus recombinant for a tumor antigen in combination with recombinant canarypox virus (ALVAC) cytokine gene delivery induces destruction of established prostate tumors. 1174 87

Cellular senescence has been proposed to be an in vitro and in vivo block that cells must overcome in order to immortalize and become tumorigenic. To characterize these pathways, we focused on changes in the cyclin-dependent kinase inhibitors and their binding partners that underlie the cell cycle arrest at senescence. As a model, we utilized normal human prostate epithelial cell (HPEC) and human uroepithelial cell (HUC) cultures. After 30-40 population doublings cells became growth-arrested in G0/1 with a threefold decrease in Cdk2-associated activity, a point defined as pre-senescence. Temporally following this growth arrest, the cells develop a senescence morphology and express senescence-associated beta-galactosidase (SA-beta-gal). Levels of p16(INK4a) and p57(KIP2) rise in HUCs during progressive passages, whereas only p16 increases in HPEC cultures. The induced expression of p57, similar to p16, produces a senescent-like phenotype. pRB, cyclin D, p19(INK4d) and p27(KIP1) decrease in both cell types. We find that p53, p21(CIP1) and p15(INK4b) are transiently elevated in HPECs and HUCs at the pre-senescent growth arrest, then return to low proliferating levels at terminal senescence. Analysis of p53, p21(CIP1), p15(INK4b), p16(INK4a), and p57(KIP2) reveals altered expression in immortalized, non-tumorigenic HPV16 E6 and E7 prostate lines and in tumorigenic prostate cancer cells. These results indicate: (i) the existence of a subset of growth inhibiting genes elevated at the onset of the senescence, (ii) a distinct class of genes involved in the maintenance of senescence, and (iii) the frequent inactivation of these pathways during immortalization.
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PMID:Role of cyclin-dependent kinase inhibitors in the growth arrest at senescence in human prostate epithelial and uroepithelial cells. 1178 34

In the present study, we examined the effects of over-expression of the potential tumor suppressor gene IGFBP-rP1/mac25 on cell-cycle kinetics in prostate cancer cells. The majority of the high expressing IGFBP-rP1/mac25 cell population was located in the G1 and sub-G0/G1 peaks; synchronizing cells in G2/M with nocodazole demonstrated the high expressing IGFBP-rP1/mac25 clones were delayed in the G1 phase of the cell cycle. Unscheduled expression of cyclin A in the sub-G0/G1 peak occurred in the IGFBP-rP1/mac25 clones. Immunoblots showed decreased cyclin D1 and p21 and increased cyclin E, p16, and p27 in the high expressing IGFBP-rP1/mac25 clones compared to the control cells. Cyclin D1/cdk-4,6 and cyclin E/cdk-2 kinase activities decreased but cyclin A/cdk-2 kinase activity increased for the high expressing IGFBP-rP1/mac25 clones compared to control cells. A pRb immunoprecipitation demonstrated more binding of E2F-1 to pRb in the high expressing IGFBP-rP1/mac25 clones than in control cells. Finally, cell senescence, as assessed by senescence-associated beta-galactosidase, demonstrated significantly more staining in the IGFBP-rP1/mac25 cells than control cells. These results suggest that IGFBP-rP1/mac25 alters the cell cycle kinetics of the M12 prostate cell line by delaying the cells in the G1 phase of the cell cycle. In addition, the appearance of cyclin A in the sub-G0/G1 phase of the cell cycle and the increased kinase activity of cyclin A/cdk-2 in the IGFBP-rP1/mac25 clones suggests that cyclin A is associated with the apoptotic cells.
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PMID:Over-expression of insulin-like growth factor binding protein-related protein-1(IGFBP-rP1/mac25) in the M12 prostate cancer cell line alters tumor growth by a delay in G1 and cyclin A associated apoptosis. 1179 Nov 84

Direct transrectal delivery of therapeutic genes utilizing adenoviral vectors for advanced prostate cancer may offer effective treatment at the molecular level. Large animal models to assess feasibility and the intraprostatic and systemic dissemination patterns of these vectors have not been reported. For these studies, a replication-deficient (E1(-)/E3(-)) recombinant adenovirus (AdRSVlacZ) expressing bacterial beta-galactosidase (beta-gal) was delivered under transrectal ultrasound guidance. Two prostate biopsies, followed by concurrent injection of 4.8 x 10(9) pfu of the adenoviral vector divided into either 1 or 2 mL of diluent, were performed (n=4). Swabs of the rectum, sputum, and urine were collected and after 72 hours, the animals were sacrificed. Specimens were assayed for the presence of virus and beta-gal activity. Rectal swabs were transiently positive, whereas urine and sputum samples showed no detectable vector throughout the experiment. Beta-gal activity was observed at the prostate injection sites with detectable activity noted up to 7.5 mm away from the injection site. Systemic dissemination was observed regardless of the injected volume. In conclusion, transrectal prostate biopsy with concurrent prostate injection is a feasible method to deliver therapeutic adenoviral vectors for the treatment of prostate cancer; however, systemic distribution and temporary rectal shedding of virus should be anticipated.
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PMID:Transrectal gene therapy of the prostate in the canine model. 1185 37

To date, there is no effective therapy for hormone-independent prostate cancer. Therefore, as a new strategy for refractory cancer, gene therapy is showing increasing promise. In this study, we attempted to use a nonviral gene transfer system, in vivo electroporation, in prostate cancer cell PC-3 xenografts with the wild-type p53 (wt-p53) gene, as gene therapy for hormone-independent prostate cancer. To evaluate this in vivo gene transfer method, the beta-galactosidase gene was transfected into xenografts by electroporation. Then, the efficiency of transfection of exogenous p53 gene by electroporation was confirmed by reverse transcription-PCR, which indicated that p53 mRNA was present in samples from xenografts. Next, to estimate the reduction of prostate cancer xenografts by this method, we measured the size of PC-3 xenografts in nude mice after electroporation with the wt-p53 gene. The growth of tumors was markedly suppressed by wt-p53 gene transfection by electroporation compared with transfection of mutated type p53 gene (P = 0.0027) or vector only (P = 0.0015). Furthermore, histological specimens revealed increased apoptotic cell death in p53-transfected tumors. These results suggest that it is possible to transfer wt-p53 into prostate cancer xenografts using electroporation and to suppress the growth of tumors; they, furthermore, suggest that this system might be used for local advanced hormone-independent prostate cancer.
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PMID:Inhibition of growth of human prostate cancer xenograft by transfection of p53 gene: gene transfer by electroporation. 1246 20

This present study evaluates the potential of adenovirus-mediated gene transfer (AMGT) to the prostate of normal laboratory beagles. Many morphological and histological similarities can be noted between dog and human prostate. Moreover, dogs can spontaneously develop prostate cancer with a clinical and biological outcome identical to that in man. Firstly we showed the capacity of human adenovirus to infect canine prostatic cells in vitro. Secondly, we injected transrectally in the dogs' prostates 2x10(9) plaque forming units of a first generation recombinant adenovirus vector harboring the reporter gene beta-galactosidase (AdRSVbetagal). Seven days after the adenoviral delivery, we observed expression of the transgene in both prostates, and exclusively in epithelial cells. Despite a cellular and a humoral immune response, the infusion appeared safe, since the dogs had no fever and presented no urinary symptoms. This study constitutes the first evaluation of AMGT in dog prostate and provides a basis for gene therapy treatment of prostate carcinoma-bearing patients.
Prostate Cancer Prostatic Dis 1999 Jan
PMID:Adenovirus-mediated gene transfer in dog prostate: a preclinical study of a relevant model system for gene therapy of human prostatic cancer. 1249 63


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