New concepts in studying the control of normal and cancer growth of the prostate.
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Androgens↗
Biomedical subjects
K J Pienta
Publications and source records attributed to K J Pienta.
The role of the nuclear matrix in the organization and function of DNA.
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Animals↗
A structural analysis of the role of the nuclear matrix and DNA loops in the organization of the nucleus and chromosome.
The interphase nucleus is characterized by a nuclear matrix structure that forms a residual scaffolding composed of approximately 10% of the total nuclear proteins. The nuclear matrix contains residual elements of the pore-complex and lamina, the nucleolus, and an intranuclear fibrous network that provides the basic shape and structure of the nucleus. In the interphase nucleus this nuclear matrix has been reported to be a central element in the organization of DNA loop domains and to contain fixed sites for DNA replication and transcription. In this study, we have analysed the role of the nuclear matrix and the DNA loop domains in the organization and structure of the number 4 human chromosome. A model is proposed that closely approximates the observed structural dimensions of this chromosome. The model is composed of 30 nm diameter filaments formed from a solenoid of six nucleosomes per turn. This 30 nm solenoid filament is organized as loops of DNA each containing approximately 60 000 base-pairs; each loop is anchored at its base to the nuclear matrix. A radial loop model containing 18 of these loops per turn forms a new unit of chromosome structure termed the miniband. Approximately 106 of these minibands are arranged along a central axis to form the final chromatid. The role of the nuclear matrix in this organization is presented. The accuracy of the proposed model is tested by comparing its features with the known properties of the number 4 human chromosome.
Cell Nucleus↗
Hormone resistance in prostate cancer.
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Androgen Antagonists↗
A new concept in cancer care: the supportive care program.
This article describes the findings of a pilot program designed to enter advanced prostate cancer patients into the hospice benefit while they are still being actively treated, but in situations where treatment is known to be primarily palliative in nature. The supportive care program (SCP) combines the medical model's goal to prolong life with the goal of hospice to palliate symptoms and improve quality of life (QOL). The concept of a SCP was developed to create a team approach where advanced prostate cancer patients who are starting investigational chemotherapy are concurrently enrolled into a hospice program. The objectives were to identify whether SCP improved QOL and continuity of care while remaining cost-effective. Data were collected on patient quality of life, performance status, use of health care resources, and costs for the 36 enrolled patients. A comparison was made to a matched set of 23 control patients. Our findings indicate that the SCP contributes to continuity of care while being cost-effective.
Aged↗
The effect of amiloride on the metastatic properties of prostate cancer in the Dunning rat model.
Most deaths from cancer result from the metastatic spread of the disease. The antidiuretic amiloride has been shown to inhibit tumor growth and metastasis in several tumor systems. The object of these studies was to examine the effect on the in vitro and in vivo tumor growth and metastasis in the MatLyLu subline of the Dunning model of rat prostate cancer. In vitro, amiloride was found to have cytotoxic effects only at high concentrations, with an IC50 of 100 microg/ml. In vitro analysis of the ability of amiloride to inhibit invasion of MLL cells demonstrated that this drug was ineffective at all concentrations examined. In vivo, amiloride did not inhibit tumor growth or metastases development. Our studies demonstrate that amiloride does not have activity in this model of prostate cancer and suggest it may not be an appropriate therapy for the treatment of prostate cancer.
Amiloride↗
The effect of hydrazine sulfate on prostate cancer growth.
Prostate cancer remains the most commonly diagnosed cancer in American males and is the second leading cause of cancer death in this group. Hydrazine sulfate, an inhibitor of gluconeogenesis, has been proposed as a means to improve nutritional status and improve survival in patients with solid tumors. We investigated the effects of hydrazine sulfate on both in vitro and in vivo models of prostate cancer. We examined the cytotoxicity of hydrazine sulfate in both human (LNCaP and PC-3) and animal (MAT-LyLu) prostate cancer cell lines. No growth inhibition was observed. In vivo, hydrazine sulfate did not suppress the growth of implanted Dunning rat prostate MAT-LyLu cells. Hydrazine sulfate does not have activity in these models of prostate cancer and may not be an appropriate therapy for patients with prostate cancer.
Animals↗
The study of gemcitabine in combination with other chemotherapeutic agents as an effective treatment for prostate cancer.
BACKGROUND: Gemcitabine has demonstrated clinical activity against several common cancers. Our studies examine the ability of gemcitabine, both alone and in combination with other chemotherapeutic agents, to inhibit the in vitro and in vivo growth of several prostate cancer cell lines. MATERIALS AND METHODS: Cultures of LNCaP, PC-3 or MLL cells were exposed to either gemcitabine or other appropriate agents for specified amounts of time. Cells were lysed and nuclei counted utilizing a Coulter Counter. For in vivo experiments, animals were injected with 1 x 10(5) MLL cells subcutaneously into the right flank. Animals were treated as indicated for 14 days. Tumors were then excised, weighed and measured. RESULTS: In both human (PC-3 and LNCaP) and rat prostate (MLL) cancer cell lines our studies demonstrated gemcitabine had a strong effect in vitro, with an IC50 of approximately 500 nM in the human lines and 10 nM in MLL cells. In vivo, studies using the Dunning prostate cancer model in Copenhagen rats resulted in a dose response inhibition of tumor growth, with an 80% decrease in tumor size in rats treated with gemcitabine at 10 mg/kg. CONCLUSIONS: Our results demonstrated the potent activity of gemcitabine against prostate cancer in the Dunning rat model and suggest the addition of paclitaxel may not aid in this activity.
Animals↗
Prostate cancer cell adhesion to quiescent endothelial cells is not mediated by beta-1 integrin subunit.
BACKGROUND: Previous studies have reported that tumor cells' adhesion to quiescent endothelial cell is mediated by beta-1 integrins. The aim of this study was to determine the role beta-1 integrins play in prostate cancer cell adhesion to human bone marrow endothelial cells (HBME) and human aortic endothelial cells (HAEC). MATERIALS AND METHODS: A well described blocking antibody to beta-1 integrin subunit was used in adhesion assays to determine the role of beta-1 integrin subunit in the adhesion of PC-3 cells to both HBME cells and HAEC. RESULTS: Antibody to the beta-1 integrin subunit failed to reduce PC-3 adhesion to HBME and HAEC, yet this same antibody significantly reduced adhesion of PC-3 cells to fibronectin coated wells. CONCLUSIONS: The data suggest that metastasis of prostate cancer cells to bone may be mediated, in part, by preferential adhesion to HBME cells; but beta-1 integrins most likely are not involved in this interaction.
Antibodies↗
Establishment and characterization of a new human prostatic cancer cell line: DuCaP.
BACKGROUND: The lack of appropriate, clinically relevant, cell-based model systems has limited prostate cancer research and the development of new therapeutic modalities. Here we report the isolation and characterization of a new adherent prostate cancer cell line, derived from the dura mater of a cancer patient. METHODS: Prostate cancer tissue was harvested at autopsy from a metastatic lesion to the dura mater of a patient with hormone refractory prostate cancer. This tissue was xenografted into SCID mice and later harvested and plated on tissue culture dishes. For characterization, soft agar clonegenic assay, in vivo xenograft growth, in vitro doubling time, karyotype analysis, immunocytochemistry for cytokeratin-18, androgen receptor, and PAP (prostatic acid phosphatase) expression, RT PCR for PAP, PSMA (prostate specific membrane antigen), expression and northern and western blot analysis to determine expression of Rb and p53, were performed. RESULTS: DuCap grows in vitro (passage 55), forms colonies in soft agar, produces tumors in SCID mice (xenograft passage 12), and is androgen sensitive. DNA content was hypertriploid. PSA was detected in mouse serum and media. Cells were AR, PAP and cytokeratin-18 positive by immunocytochemistry. PSMA and PAP were detected by RT-PCR. AR, P53, and Rb were expressed in Northern blot analysis. P53 protein was detected in Western blot analysis but Rb protein was not. CONCLUSIONS: This cell line exhibits many phenotypic characteristics of clinical prostate carcinoma, including expression of PSA, PSMA, PAP and AR.
Androgens↗
VCaP, a cell-based model system of human prostate cancer.
OBJECTIVES: We report the isolation and characterization of a novel prostate cancer cell line derived from a vertebral metastatic lesion, Vertebral-Cancer of the Prostate (VCaP). METHODS: Prostate cancer tissue was harvested at autopsy from a metastatic lesion to a lumbar vertebral body of a patient with hormone refractory prostate cancer. This tissue was aseptically xenografted into SCID mice and later harvested and plated on tissue culture dishes. For characterization, soft agar clonegenic assay, in vivo xenograft growth, in vitro doubling time, karyotype analysis, immunocytochemistry for cytokeratin-18 expression immunochemistry for PSA (prostate specific antigen), RT PCR for PAP (prostatic acid phosphatase) and northern blot and western blot analysis to determine expression of Rb and p53, were performed. Androgen receptor expression was measured by transient transfection with a luciferase reporter construct. RESULTS: VCaP cells are immortal in vitro and can be passaged serially in vivo. They express large quantities of prostate specific antigen (PSA). This cell line also expresses prostatic acid phosphatase (PAP), cytokeratin-18 and the androgen receptor, and is androgen sensitive in vitro and in vivo. CONCLUSIONS: This cell line was derived from a metastatic tumor to the vertebrae of a prostate cancer patient. It exhibits many of the characteristics of clinical prostate carcinoma, including expression of PSA, PAP, and AR. We believe that VCaP will be a useful addition to the existing models of prostate cancer, and enable more advanced study of the mechanisms of prostate cancer progression and metastasis.
Acid Phosphatase↗
The effect of maltose tetrapalmitate (MTP) on prostate cancer growth in vivo and in vitro.
Maltose tetrapalmitate (MTP), a non-toxic synthetic glycolipid analog of lipid A, has been shown to have antitumor activity in tumor-transplanted animals. Its mode of action has been postulated to be as an immunoadjuvant or as an anti-angiogenesis agent. MTP has been shown to have antitumor properties in lung, bladder, mammary, colon, liver and soft tissue tumors, but its action on prostate cancer has not yet been investigated. The effect of MTP alone and in combination with hydrocortisone hemisuccinate on prostate cancer and the ability of MTP to inhibit angiogenesis were examined in this study. In vitro, MTP was minimally cytotoxic to rat prostate cancer cells and to bovine and human endothelial cells at high concentrations. In the angiogenesis inhibition assays, the MTP alone exhibited no anti-angiogenesis effect and significant anti-angiogenesis activity only when combined with hydrocortisone hemisuccinate at high doses. In vivo, however, MTP demonstrated significant inhibition of prostate cancer growth. These results suggest that MTP decreases prostate cancer growth in vivo but it is not an angiogenesis inhibitor in rat prostate cancer.
Adenocarcinoma↗
Pentosan inhibits angiogenesis in vitro and suppresses prostate tumor growth in vivo.
Pentosan polysulfate (PPS) is a highly negatively charged polysaccharide which has activity against multiple tumor types in the preclinical setting. We demonstrate here that Pentosan inhibits the growth of the anaplastic Dunning R3327 rat prostate adenocarcinoma MAT-LyLu when treatment was started when the tumor was not palpable but has little effect against established tumors. This inhibition may be mediated by the effect of Pentosan on endothelial cells. Pentosan, in combination with hydrocortisone, inhibits endothelial cell motility and tubule formation in vitro and inhibits capillary formation in the chicken chorioallantoic membrane (CAM) assay. These data suggest that Pentosan may be a potent inhibitor of tumor-associated angiogenesis and may be an effective agent for the prevention and/or suppression of prostate cancer growth.
Adenocarcinoma↗
Tumor-associated angiogenesis in prostate cancer.
All solid tumors require the induction of new blood vessels to grow. To begin to study this phenomenon in prostate cancer, we investigated the intensity of tumor associated angiogenesis in prostate non malignant and malignant tissue. Angiogenesis was measured by quantitating microvessels in a total of 67 patients: 23 non malignant biopsy specimens, and 34 malignant specimens from patients who had undergone prostatectomy. Angiogenic activity in prostatic cancer (prostatectomy) tissue (utilizing Factor VIII staining) was then correlated with pathological staging (Whitmore-Jewitt). Overall there appeared to be a trend of increasing microvessel count (MVC) from benign through the advancing stages of prostate cancer. Based on mean microvessel counts we were able to distinguish stage D from all other pathological stages (p = 0.004 between stages C and D). There was, however, no statistically significant difference between stage B and C. We conclude that tumor associated angiogenesis in prostate cancer may have both clinical and pathological significance in prostate cancer.
Humans↗
Immunomagnetic isolation of endothelial cells from normal rat prostate tissue.
Angiogenesis, or the process of the formation of new blood vessels, is an essential event for the successful growth of tumors in vivo. The discovery of agents which inhibit angiogenesis has been limited by the lack of available experimental endothelial cell systems which mimic specific organ- or tumor-derived endothelial cells. It is well recognized that there are measurable functional and morphological differences between normal tissue endothelium and tumor vessels, however, the cause of these differences remains unclear. We report here a technique for tissue specific endothelial cell isolation from the rat prostate utilizing immunomagnetic techniques, providing a tool for the study of endothelial cells and their inhibition.
Animals↗
The epidemiology of prostate cancer: clues for chemoprevention.
Prostate cancer exists as two different clinical entities; a "latent" or "histologic" form and a clinically evident form. While the prevalence of histologic prostate cancer is similar around the world, the prevalence of clinical cancer varies dramatically from country to country. This suggests that promotional events which contribute in the transformation of histologic cancer to clinically important cancer vary from country to country and population to population. The ultimate goal of epidemiologic studies is to identify risk factors, i.e., promotional agents, for prostate cancer and to use this knowledge for disease prevention strategies.
Antineoplastic Agents↗
An in vitro and in vivo study of antitumor effects of genistein on hormone refractory prostate cancer.
Hormone refractory prostate cancer remains an incurable disease. Newer agents with more activity are required. Genistein is a flavone compound with anti-tumor activity against various tumor systems in vitro. This study is undertaken to assess the efficacy of genistein against hormone refractory prostate cancer. In vitro, genistein appears to be cytotoxic to both the rat prostate cancer cell line MAT-LyLu and the human prostate adenocarcinoma cell line, PC-3. In vivo, however, genistein failed to significantly inhibit the growth of subcutaneously implanted MAT-LyLu cells. More information regarding the pharmacokinetics and bio-availability of genistein is needed to determine if this is an active agent in human metastatic prostate cancer.
Adenocarcinoma↗
The effects of omega-3 and omega-6 fatty acids on in vitro prostate cancer growth.
Dietary intake of essential fatty acids (EFA) may play a role in prostate cancer cell proliferation. Epidemiological studies have demonstrated that men whose dietary intake is high in omega-3 fatty acid (FA) composition have a lower incidence of clinical prostate cancer, suggesting that external factors such as diet may play an important role in development and growth of prostate cancer. Furthermore, in prostate cancer cell lines, omega-6 and omega-3 FAs have demonstrated promotional and inhibitory effects respectively. To investigate the effects of dietary fats on nontumorigenic prostate cell growth we conducted in vitro studies with human metastatic PC-3, LNCaP and TSU prostate cell lines, the rat metastatic Mat-Ly-Lu cell line and rat non-metastatic epithelial cell lines EPYP1, EPYP2 and EPYP3. Cell lines were treated with linoleic acid (LA), an omega-6 FA (n-6), as well as linolenic (LLA) and eicosapentaenoic (EPA) acids, which are both omega-3 FAs (n-3). All cell lines were treated with 10% and 0.5% serum supplemented media plus fatty acid for comparison. Our results demonstrate that linoleic acid(n-6) has promotional effects at doses of 1-100ng/ml in all cell lines with the exception of EPYPl. Experiments with linolenic acid (n-3) demonstrated consistent growth promotion in all cell lines examined with the exception of the EPYP2 cell line in which there was no significant effect. EPA had no effect in culture media supplemented with 10% serum, while in media containing 0.5% serum this FA demonstrated significant promotion in all human lines. Previous studies have indicated that EPA should inhibit human prostate cancer growth in vitro, however our results demonstrated promotion at low concentrations (lng/ml). At higher concentrations, EPA did inhibit prostate cell growth. These data indicate low levels of dietary fat, regardless of composition, may play a role in prostate cancer proliferation and could be an avenue for therapeutic intervention.
Animals↗