Biomedical subjects

T C Thompson

Publications and source records attributed to T C Thompson.

At least 55 records · Page 3Linked to original sources

PubMed1999

Caveolin-1, a metastasis-related gene that promotes cell survival in prostate cancer.

Metastasis represents the ultimate target in cancer therapy as this complex biological process is the direct cause of mortality for a variety of human malignancies. The current high level of mortality from prostate cancer results in large part from the inexorable growth of overt or occult metastasis present at the time of diagnosis. Currently, there are no curative therapies for metastatic prostate cancer. To better understand the metastatic phenotype in prostate cancer, we developed a strategy to identify mRNAs that are expressed differentially in cell lines derived from primary versus metastatic mouse prostate cancer using differential display-PCR. In using this system a number of metastasis-related sequences were identified including a cDNA that encodes caveolin-1. Caveolin-1 was found to be overexpressed not only in metastatic mouse prostate cancer, but also in human metastatic disease. Recent studies have indicated that suppression of caveolin-1 expression induces androgen sensitivity in high caveolin-1, androgen-insensitive mouse prostate cancer cells derived from metastases. Conversely, overexpression of caveolin-1 leads to androgen insensitivity in low caveolin, androgen-sensitive mouse prostate cancer cells. Caveolin-1, therefore, is both a metastasis-related gene as well as a candidate androgen resistance gene for prostate cancer in man. Interestingly, recent studies also point to a potential role for caveolin-1 in the resistance of various malignancies to multiple antineoplastic agents. The linkage of caveolin-1 expression with the androgen-resistant phenotype in prostate cancer and the multidrug resistance phenotype in various solid tumors establishes a novel paradigm for understanding these clinically important and now potentially related processes in malignant progression.

Journal Article↗

PubMed1999

Adenovirus-mediated interleukin-12 gene therapy for prostate cancer: suppression of orthotopic tumor growth and pre-established lung metastases in an orthotopic model.

Interleukin-12 (IL-12) can elicit potent antitumoral effects that involve the recruitment of specific immune effector cells. We investigated the efficacy of a single injection of a recombinant adenovirus expressing murine IL-12 (AdmIL-12) directly into orthotopic mouse prostate carcinomas generated from a poorly immunogenic cell line (RM-9) derived from the mouse prostate reconstitution system. Significant growth suppression (> 50% reduction of tumor weight) and increased mean survival time (23.4 to 28.9 days) were observed compared with controls. Suppression of pre-established lung metastases was also observed following the injection of AdmIL-12 into the orthotopic tumor. Cytolytic natural killer cell activity was markedly enhanced 1-2 days after virus injection. Immunohistochemical analysis showed significantly elevated intratumoral infiltration of CD4+ and CD8+ T cells 7 days after virus injection. However, splenocyte-derived cytotoxic T lymphocytes were not detected during the 14 days following treatment. Increased numbers of nitric oxide synthase-positive macrophages were seen in the AdmIL-12 treated group 7 days following injection. Systemic inhibition of natural killer cells with antiasialo-GM1 serum led to increased numbers of lung metastases in AdmIL-12-treated orthotopic tumors but did not affect local tumor growth. In this model system the antitumor effects of a single injection of adenovirus-mediated IL-12 appears to be based to a large extent on the activation of nitric oxide synthase in macrophages and possibly T cell activities, whereas the relatively early cytolytic activity of natural killer cells are largely but not exclusively responsible for the antimetastatic effects.

Adenoviridae↗

PubMed1999

Novel regulation of type IV collagenase (matrix metalloproteinase-9 and -2) activities by transforming growth factor-beta1 in human prostate cancer cell lines.

The type IV collagenases/gelatinases matrix metalloproteinase-2 (MMP-2) and MMP-9 play a variety of important roles in both physiological and pathological processes and are regulated by various growth factors, including transforming growth factor-beta1 (TGF-beta1), in several cell types. Previous studies have suggested that cellular control of one or both collagenases can occur through direct transcriptional mechanisms and/or after secretion through proenzyme processing and interactions with metalloproteinase inhibitors. Using human prostate cancer cell lines, we have found that TGF-beta1 induces the MMP-9 proenzyme; however, this induction does not result from direct effects on gene transcription but, instead, through a protein synthesis-requiring process leading to increased MMP-9 mRNA stability. In addition, we have examined levels of TGF-beta1 regulation of MMP-2 in one prostate cancer cell line and found that TGF-beta1 induces higher secreted levels of this collagenase through increased stability of the secreted 72-kDa proenzyme. These results identify two novel nontranscriptional pathways for the cellular regulation of MMP-9 and MMP-2 collagenase gene expression and activities.

Collagenases↗

PubMed1999

Elevated levels of circulating interleukin-6 and transforming growth factor-beta1 in patients with metastatic prostatic carcinoma.

PURPOSE: Specific cytokines have been found to be secreted by and influence the growth of prostate cancers in cell culture. Interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), granulocyte macrophage-colony stimulating factor (GM-CSF) and transforming growth factor-beta1 (TGF-beta1) have all been closely associated with prostate cancer. We analyzed the levels of these cytokines in the systemic circulation of patients with varying stages of prostate cancer compared to controls. MATERIALS AND METHODS: Serum IL-6, TNFalpha and GM-CSF were measured using commercially available enzyme linked immunosorbent assays in 5 groups of patients, including controls-19 men presenting to prostate cancer screening with normal digital rectal examination and serum prostate specific antigen (PSA) no greater than 2.0 ng./ml., stage pT2-19 with cancer confined to the prostate in the radical prostatectomy specimen, stage pT3-10 with extraprostatic extension and/or seminal vesicle involvement, stage N1-12 with lymph node metastases at pelvic lymph node dissection, and stage M1-9 with bone metastases. Platelet poor plasma TGF-beta1 was measured using a commercially available enzyme linked immunosorbent assay in controls and patients with stage M1 disease only because it was not available for patients with stages pT2, pT3 and N1 disease. No patient had a history of any other malignancy. All blood specimens were collected before surgery and/or androgen ablation. Statistical analysis was done with the Kruskal-Wallis analysis of variance. RESULTS: Serum IL-6 and platelet poor plasma TGF-beta1 were significantly elevated in patients with clinically evident metastases (p = 0.0008 and 0.0412, respectively) while serum GM-CSF and TNFalpha were not. IL-6 and TGF-beta1 correlated with increasing serum PSA (p = 0.0335 and 0.0386, respectively). GM-CSF did not correlate with PSA or age. In multivariate analysis TNFalpha correlated with age but not PSA. CONCLUSIONS: IL-6 and TGF-beta1 correlate with tumor burden as assessed by serum PSA or clinically evident metastases. Further research is needed to determine the response to androgen ablation as well as the source(s) and actions of these cytokines.

Adult↗

PubMed1999

In situ gene therapy for prostate cancer.

The natural history of prostate cancer presents a dilemma for those interested in developing effective treatment for the disease. When the disease is localized (and therefore potentially curable by localized therapies), it is often of uncertain biological potential and in many cases will not progress to clinical significance. However, both experimental and clinical studies indicate that prostate cancer can metastasize early and/or from relatively small foci of prostate cancer within the gland and is often systemic at the time of diagnosis. Unfortunately, there are no curative therapies for metastatic prostate cancer. In general, currently used therapies with the potential to be curative involve a single cytoablative modality (radical prostatectomy and irradiation therapy) and are directed exclusively at the malignant cells within the prostate gland. At present the widespread use of these treatments alone has not resulted in substantial reduction in mortality from the prostate cancer. Gene therapy used alone or as an adjuvant approach could, at least conceptually, provide a rational solution for the prostate cancer dilemma. With gene therapy, it may be possible to treat localized and systemic disease effectively and simultaneously. Indeed, in situ gene therapy protocols in which viral vectors are used to transduce specific genes that generate cytotoxic activity and/or systemic immunity to the cancer offer hope for significantly reducing the mortality from this disease. This commentary discusses early studies specifically aimed toward developing in situ-based gene therapies that can generate cytotoxic activities in localized prostate cancers and/or the generation of an immune response in the primary tumor that would affect systemic disease.

Adenoviridae↗

PubMed1999

Levels of expression of p27KIP1 protein in human prostate and prostate cancer: an immunohistochemical analysis.

p27KIP1 is a member of the CIP/KIP family of cyclin-dependent kinase inhibitory proteins that negatively regulate cell proliferation. Recent studies reported decreased p27 expression in breast and colon carcinomas and found that the loss of p27 is associated with a poor prognosis. We report here the results of our immunohistochemical analysis of p27 in human prostate cancer. Formalin-fixed, paraffin-embedded, whole-mount sections of prostate cancer from 73 selected patients treated by radical retropubic prostatectomy were obtained from the Department of Pathology, The Methodist Hospital, Houston, Texas. Ten histologically normal and nine high-grade prostatic intraepithelia neoplasia foci were selected from these whole-mount sections, and nine cases of transplant donor prostates were chosen as controls. Also, 10 prostate cancer metastatic lymph nodes were used to compare with the primary cancer group. Sections were immunostained with a monoclonal antibody against p27 protein using the avidin-biotin complex immunohistochemical method. Immunoactivity was evaluated without knowledge of follow-up and recorded as the p27 labeling index (LI) (defined as the percentage of p27-positive cells among epithelia of the same category). The p27 (LI) in normal prostatic epithelia was 86.4+/-3.5% (the mean +/- the standard error of the mean). In contrast, the p27 immunoreactivity was significantly lower in cancers (LI: 43.5 +/-3.7%, P < .001) and in the high-grade prostatic intraepithelial neoplasia group (LI: 59.3 +/- 3.2%, P < .05). Expression of p27 in the metastatic lymph node group was significantly lower than in the other groups, including the prostate cancer cases and the cases of high-grade intraepithelial neoplasia (LI, 7.0%; P = .05). There was no association of the mean p27 LI with progression after radical prostatectomy. Nonrecurrent cases, with a mean follow-up time of greater than 5 years (n = 45), equalled 41.9%; recurrent cases, with a mean follow-up time of 18.3 months (n = 28), equalled 40.0%. The mean p27 LI was not associated with pathologic stage. Organ-confined specimens (n = 21) equalled 34.2%; cases of extraprostatic extension (n = 24) equalled 46.5%; and samples showing seminal vesicle involvement (n = 14) equalled 47.6%. In 14 cases with lymph node metastases, the mean p27 LI was 48.1% in the primary cancer (P = .2322). There was no association of the mean p27 LI with the Gleason score (P = .4747) nor with the clinical stage (P = .9914).

Cell Cycle Proteins↗

PubMed1999

Metastasis-related genes in prostate cancer.

The identification of genes specifically related to the development of metastatic disease in prostate cancer is complicated by tumor cell heterogeneity and the presence of expressed sequences that are not related to metastasis. A system was designed to minimize these complications using differential display-polymerase chain reaction (DD-PCR) together with genetically paired cell lines derived from primary mouse prostate cancer and their associated metastases generated in vivo by the metastatic mouse prostate cancer reconstitution model. Using this system, a number of metastasis-related sequences were identified, including a cDNA that encodes caveolin-1.

Animals↗

PubMed1998

Neuropeptides induce Mr 92,000 type IV collagenase (matrix metalloprotease-9) activity in human prostate cancer cell lines.

The type IV collagenases matrix metalloprotease (MMP)-2 and MMP-9 are linked with a wide array of biological activities, including tumor invasion, metastasis, and angiogenesis. Here, we report that neuropeptide hormones, which are present in prostatic adenocarcinomas, can stimulate secreted activity of MMP-9 in human prostate cancer cell lines. Northern blotting analyses demonstrated that neuropeptide stimulation lead to elevated mRNA levels of MMP-9 but not MMP-2. Further assays of MMP-9 promoter activation and a nuclear run-off indicated that neuropeptide induction of MMP-9 expression occurs at the level of transcription. These data indicate that neuropeptides can regulate MMP activity, which, in turn, could facilitate prostate cancer progression.

Adenocarcinoma↗

PubMed1998

Reduced lysyl oxidase messenger RNA levels in experimental and human prostate cancer.

To identify genes associated with prostate cancer progression, we developed a strategy involving the use of differential display PCR and a panel of genetically matched primary tumor- and metastasis-derived mouse prostate cancer cell lines. We analyzed sequences that were differentially stimulated by transforming growth factor-beta1 in primary tumor-versus metastasis-derived cell lines, based on our previous studies indicating that acquisition of differential responses to this growth factor could result in phenotypic traits that facilitate tumor metastasis from specific cell clones within the primary tumor. Using this system, we isolated and sequenced a cDNA fragment that encoded mouse lysyl oxidase (LO) and was induced by transforming growth factor-beta1 in primary tumor but not in metastasis-derived cells. Northern blotting analysis revealed increased LO expression in a panel of primary tumor cell lines but significantly reduced or nondetectable expression in their matched metastatic counterparts. Further in situ hybridization analysis revealed LO expression in normal mouse prostate epithelium but, in most cases, progressive loss of expression in primary prostate cancer and associated metastatic lesions. Importantly, in situ hybridization studies of normal human prostate and prostate malignancies revealed a similar loss of expression during progression to metastasis. The progressive loss of LO expression during prostate cancer progression provides information that may increase our understanding of the mechanisms that underlie this disease. In addition, LO may provide a useful molecular marker and/or establish a novel therapeutic target for prostate cancer.

Animals↗

PubMed1998

Assessment of the biologic markers p53, Ki-67, and apoptotic index as predictive indicators of prostate carcinoma recurrence after surgery.

BACKGROUND: This study was designed to evaluate the potential of the molecular and cellular markers p53, Ki-67, and apoptotic index (AI) as adjuncts to the commonly available variables of tumor grade, clinical stage, and serum prostate specific antigen to predict prostate carcinoma recurrence after radical prostatectomy. METHODS: Representative punch biopsy specimens of prostate carcinoma from whole mount paraffin blocks were evaluated from 47 men who underwent radical prostatectomy. Two groups were defined: those without evidence of prostate carcinoma recurrence after 5 years of follow-up (N = 30) and those with carcinoma recurrence (N = 17). Gleason grade, clustered p53 immunostaining, Ki-67 immunostaining, and AI were determined by standard techniques. RESULTS: All variables tested were associated with disease recurrence by univariate analysis: AI (P = 0.005), clustered p53 immunostaining (P = 0.0070), and Ki-67 immunostaining (P = 0.0390). Using multivariate analyses that included each biomarker with routinely available features, only AI (P = 0.0234) and clustered p53 immunostaining (P = 0.0389) added independent prognostic information (Ki-67 immunostaining, P = 0.1285). In the final logistic regression model that included standard variables with AI and p53, only AI reached statistical significance (P = 0.0332). CONCLUSIONS: The continued assessment of additional biomarkers for prostate carcinoma recurrence is important to identify better those patients who may be candidates for early adjuvant therapy and also to further our understanding of the neoplastic potential of a particular malignancy.

Aged↗

PubMed1998

Quantitative immunohistochemical analysis of insulin-like growth factor binding protein-3 in human prostatic adenocarcinoma: a prognostic study.

PURPOSE: We sought to characterize and quantitate the expression of IGFBP-3 in adenocarcinoma of the prostate and to test whether it correlated with tumor differentiation determined by Gleason grade. We also investigated the potential of using IGFBP-3 as a prognostic indicator of clinically localized prostate cancer. MATERIALS AND METHODS: Initially we evaluated the expression of IGFBP-3 in six normal and twenty neoplastic prostates using standard immunohistochemical techniques (study 1). We then obtained radical prostatectomy specimens from twenty-four patients with a preoperative diagnosis of clinically localized prostate adenocarcinoma and five year follow up information, and nine normal prostates from organ donors or from patients undergoing cystoprostatectomy (study 2). All specimens were immunostained with a polyclonal anti-human IGFBP-3 antibody. A single pathologist reviewed all sections and assigned a Gleason grade to each cancer focus. Using computer-assisted video image analysis, we quantified the intensity of IGFBP-3 immunostaining of each cancer focus and of normal controls. RESULTS: Normal prostatic epithelium showed intense cytoplasmic IGFBP-3 staining. The stromal compartment showed less intense staining, although there were occasional areas with strong immunoreactivity. The cellular distribution of IGFBP-3 staining in prostatic adenocarcinoma was comparable to normal tissue; however, the intensity of detectable staining in neoplastic epithelial cells was significantly decreased. Two foci of prostatic intraepithelial neoplasia (PIN) demonstrated IGFBP-3 immunoreactivity decreased in comparison to normal epithelium, but greater than prostatic adenocarcinoma. Histologically normal epithelium surrounding cancer foci also showed decreased immunostaining for IGFBP-3 compared with normal prostate. The marked decrease in immunostaining intensity of IGFBP-3 in prostate adenocarcinoma was not associated with Gleason grade or with clinical outcome. CONCLUSION: Malignant transformation of prostatic epithelium was associated with a significant decrease in the amount of immunoreactive IGFBP-3 (p <0.0001); however, this parameter did not correlate with Gleason grade of the tumor or with patient outcome. The decrease in immunostaining intensity of IGFBP-3 in all Gleason grades and in PIN suggests that lower expression of IGFBP-3 is an early event in prostatic carcinogenesis. The finding that decreased IGFBP-3 immunostaining did not correlate with clinical outcome suggests that this parameter is not a therapy-guiding prognostic indicator for clinically localized prostate cancer.

Adenocarcinoma↗

PubMed1998

Induction of labyrinthitis ossificans after pneumococcal meningitis: an animal model.

Newly formed disorganized bone fills the open spaces within the otic capsule in various pathologic conditions, resulting in labyrinthitis ossificans. The pathologic mechanisms of this disease remain poorly understood. To better study the sequence of events and contributing mechanisms involved in labyrinthitis ossificans, an animal model was developed. Three groups of Mongolian gerbils received either an intralabyrinthine injection of normal saline solution (group 1) or Streptococcus pneumoniae polysaccharide capsule antigens (groups 2 and 3). The temporal bones were harvested after 3 months and serially sectioned. None of the eight control animals (group 1), which received intralabyrinthine injections of normal saline solution had any histologic changes in their temporal bones. Nine of the surviving 19 animals in groups 2 and 3 had fibrosis or evidence of early ossification. A fourth group of Mongolian gerbils received two intrathecal injections of live S. pneumoniae organisms. The temporal bones were harvested after 3 months and serially sectioned. Fourteen of the surviving 15 animals had fibrosis or ossification or both. This animal model will provide a method for study of the mechanisms of labyrinthitis ossificans.

Animals↗

PubMed1998

Suppression of caveolin expression induces androgen sensitivity in metastatic androgen-insensitive mouse prostate cancer cells.

Although prostate cancer cells are often initially sensitive to androgen ablation, they eventually lose this response and continue to survive, grow and spread in the absence of androgenic steroids. The mechanism(s) that underlie resistance to androgen ablation therapy remain mostly unknown. We have demonstrated that elevated caveolin protein levels are associated with human prostate cancer progression in pathological specimens. Here we show that suppression of caveolin expression by a stably transfected antisense caveolin-1 cDNA vector converted androgen-insensitive metastatic mouse prostate cancer cells to an androgen-sensitive phenotype. Orthotopically grown tumors and low-density cell cultures derived from antisense caveolin clones had increased apoptosis in the absence of androgenic steroids, whereas similarly grown tumors and cells from vector (control) clones and parental cells were not sensitive to androgens. Studies using a representative antisense caveolin clone showed that selection for androgen resistance in vivo correlated with increased caveolin levels, and that adenovirus-mediated caveolin expression blocked androgen sensitivity. Our results identify a new candidate gene for hormone-resistant prostate cancer in man and indicate that androgen insensitivity can be an inherent property of metastatic prostate cancer.

Androgens↗

PubMed1998

Requirement for matrix metalloproteinase-9 (gelatinase B) expression in metastasis by murine prostate carcinoma.

Although a number of effective therapies are available for localized prostate cancer, metastatic prostate cancer is difficult to treat and impossible to cure. Identification of the gene products that enable a prostatic carcinoma cell to metastasize should facilitate an understanding of the processes leading to metastasis. To characterize the contribution of matrix metalloproteinase-9 (MMP-9, gelatinase B or the 92-kd type IV gelatinase/collagenase) to the development of metastasis in prostate cancer, we reduced MMP-9 expression in metastatic murine prostatic carcinoma cells using a ribozyme. The ribozyme transfected cells had lower basal levels of MMP-9 as well as decreased levels after stimulation by transforming growth factor-beta or phorbol 12-myristate 13-acetate when compared with the parental cells or with control transfectants. The cells with down-regulated MMP-9 were unable to form lung colonies in the experimental metastasis assay, whereas the controls and parental cells readily formed metastases. All cell types readily formed tumors after injection and down-regulation of MMP-9 did not adversely affect the rate of tumor growth. Thus, MMP-9 expression is required for hematogenous metastasis in a murine prostate model system raising the possibility that it may play an equivalent role in human prostate cancer.

Animals↗

PubMed1998

Elevated expression of caveolin is associated with prostate and breast cancer.

To identify genes associated with prostate cancer progression, we developed a strategy involving the use of differential display-PCR with a panel of genetically matched primary tumor- and metastasis-derived mouse prostate cancer cell lines. We isolated a cDNA fragment with homology to the mouse caveolin-1 gene. Northern blotting with this fragment revealed increased caveolin expression in metastasis-derived cell lines relative to primary tumor-derived cell lines. Western blotting with a polyclonal caveolin antibody confirmed increased caveolin protein in metastasis-derived mouse cell lines and expression in three of four human prostate cancer cell lines. Immunohistochemical analysis of a human prostate cancer cell line demonstrated a prominent granular pattern of caveolin accumulation. Subsequent analysis of mouse and human prostate specimens revealed minimal caveolin expression in normal epithelium with abundant staining of smooth muscle and endothelium. The frequency of caveolin-positive cells was increased in prostate cancer with markedly increased accumulation of caveolin and a granular staining pattern in lymph node metastatic deposits. In human breast cancer specimens, increased caveolin staining was detected in intraductal and infiltrating ductal carcinoma as well as nodal disease. Caveolin therefore appears to be associated with human prostate cancer progression and is also present in primary and metastatic human breast cancer.

Animals↗

PubMed1997

Transforming growth factor beta 1 transduced mouse prostate reconstitutions: I. Induction of neuronal phenotypes.

BACKGROUND: We previously showed that retroviral transduction of transforming growth factor beta 1 (TGF-beta 1) induces focally hyperplastic lesions resembling benign prostatic hyperplasia (BPH) and an increase in the number of ganglion-like cells in the mouse prostate reconstitution (MPR) model in vivo. In the present study we further characterize the neuronal phenotypes induced by TGF-beta 1 retroviral transduction in MPRs. METHODS: Computer-assisted morphometric analysis was used to evaluate neuronal density. Neuronal cell markers, including neurofilament, neuron-specific enolase, tyrosine hydroxylase, choline acetyltransferase, L-met enkaphaline, and serotonin, were detected by immunostaining. RESULTS: A fourfold increase in neuronal density was observed in TGF-beta 1 retrovirus-transduced MPRs. The relative frequencies of neuronal subtypes remained similar, with catecholaminergic and cholinergic neurons presenting as the most abundant. We found no evidence of infection of neurons; therefore, increased neuronal density was likely due to paracrine activities. CONCLUSIONS: Our results suggest that enforced TGF-beta 1 expression leads to growth and/or survival of both catecholaminergic and cholinergic neuronal cells in mouse prostate reconstitutions.

Acetylcholine↗

PubMed1997

Transforming growth factor beta 1 transduced mouse prostate reconstitutions: II. Induction of apoptosis by doxazosin.

BACKGROUND: To study the possible relationship between adrenergic activities and the pathogenesis of benign prostatic hyperplasia (BPH), we tested the effect of doxazosin, an alpha 1-adrenoceptor antagonist, on prostatic growth in vivo using a mouse model for BPH. METHODS: The mouse prostate reconstitution (MPR) model system with retroviral (BabeTGF-beta 1Neo) transduction of transforming growth factor beta 1 (TGF-beta 1) was used to induce focally hyperplastic BPH-like lesions and increase the number of catecholaminergic neurons. The mice were treated with daily intraperitoneal injections of doxazosin (3 mg/kg). RESULTS: Doxazosin caused a significant reduction in the wet weight of BabeTGF-beta 1-infected MPRs. The percent of PCNA-positive epithelial cells was similar in the doxazosin-treated and water only, control groups. There was a significant increase in the number of epithelial cells undergoing programmed cell death, apoptosis, in the doxazosin group (apoptotic index = 4.7 for doxazosin group vs. 3.1 for control group, P < 0.05). The doxazosin-induced apoptosis was more apparent in TGF-beta 1 transduced MPRs than BAG alpha control MPRs, and was not seen in the prostates of the adult male mice into which the MPRs were engrafted. CONCLUSIONS: Our data demonstrate a novel and potentially important biological activity of doxazosin in vivo in this mouse model of BPH.

Adrenergic alpha-Antagonists↗

PubMed1997

Adenovirus-mediated herpes simplex virus thymidine kinase gene and ganciclovir therapy leads to systemic activity against spontaneous and induced metastasis in an orthotopic mouse model of prostate cancer.

It is critical to develop new therapies, such as gene therapy, which can impact on both local and metastatic prostate cancer progression. We have developed an orthotopic mouse model of metastatic prostate cancer using a cell line (RM-1) derived from the mouse prostate reconstitution (MPR) model system. This mouse model closely simulates the anatomical and biological milieu of the prostate and allows for realistic testing of experimental gene therapy protocols. Adenovirus (ADV)-mediated transduction of the herpes simplex virus thymidine kinase (HSV-tk) gene in conjunction with ganciclovir (GCV) in this model led to significant suppression of growth and of spontaneous metastasis at 14 days post-tumor inoculation. Longer-term studies produced a significant survival advantage and a continued suppression of metastatic activity for treatment animals despite regrowth of the primary tumor. Challenge by injection of tumor cells into the tail vein following excision of treated and control s.c. primary tumors resulted in 40% reduction in lung colonization in the treatment group, indicating the possible production of systemic anti-metastatic activity following a single in situ treatment with ADV/HSV-tk + GCV in this model system.

Adenoviridae↗