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P H Lange

Publications and source records attributed to P H Lange.

At least 19 recordsLinked to original sources
PubMed1997

Cell-cell interaction in prostate gene regulation and cytodifferentiation.

To examine the role of intercellular interaction on cell differentiation and gene expression in human prostate, we separated the two major epithelial cell populations and studied them in isolation and in combination with stromal cells. The epithelial cells were separated by flow cytometry using antibodies against differentially expressed cell-surface markers CD44 and CD57. Basal epithelial cells express CD44, and luminal epithelial cells express CD57. The CD57+ luminal cells are the terminally differentiated secretory cells of the gland that synthesize prostate-specific antigen (PSA). Expression of PSA is regulated by androgen, and PSA mRNA is one of the abundant messages in these cells. We show that PSA expression by the CD57+ cells is abolished after prostate tissue is dispersed by collagenase into single cells. Expression is restored when CD57+ cells are reconstituted with stromal cells. The CD44+ basal cells possess characteristics of stem cells and are the candidate progenitors of luminal cells. Differentiation, as reflected by PSA production, can be detected when CD44+ cells are cocultured with stromal cells. Our studies show that cell-cell interaction plays an important role in prostatic cytodifferentiation and the maintenance of the differentiated state.

Androgens↗
PubMed1997

Androgenic induction of prostate-specific antigen gene is repressed by protein-protein interaction between the androgen receptor and AP-1/c-Jun in the human prostate cancer cell line LNCaP.

In exploring the possible mechanisms of androgen independence of prostate-specific antigen (PSA) gene expression, we investigated the effect of elevating AP-1 by both 12-O-tetradecanoylphorbol 13-acetate (TPA) treatment and transfection of the c-Jun expression vector in LNCaP cells. Transcription of PSA is initiated when ligand-activated androgen receptor (AR) binds to a region in the PSA promoter that contains an androgen-responsive element (ARE). It was found that TPA inhibited androgen-induced PSA gene expression by a mechanism that did not alter nuclear levels of AR protein. Overexpression of AP-1 (jun and fos proteins) also inhibited androgen-induced PSA promoter activity. These observations were apparently related to the disruption of AR.ARE complexes as demonstrated by the results of electrophoretic mobility shift assays. Specifically, c-Jun inhibited the formation of AR.ARE complexes and conversely that AR-glutathione S-transferase proteins inhibited the formation of c-Jun.TPA-responsive element (TRE) complexes. Consistent with the inhibitory effect of both proteins, anti-c-Jun antibody blocked the inhibition of AR.ARE complex formation by c-Jun. A similar, but less marked, effect was obtained when anti-AR antibody was used to prevent AR inhibition of c-Jun.TRE complex formation. These findings together with results obtained from co-immunoprecipitation experiments strongly suggest that mutual repression of DNA binding activity is due to direct interaction between the two proteins and that the degree of repression may be determined by the ratio of AR to c-Jun. The mechanism of repression studied in mutant analysis experiments yielded evidence of an interaction between the DNA- and ligand-binding domains of AR and the leucine zipper region of c-Jun. Thus, the AR is similar to other nuclear receptors in its ability to interact with AP-1. This association provides a link between AP-1 and AR signal transduction pathways and may play a role in the regulation of the androgen-responsive PSA gene.

Androgens↗
PubMed1997

Characterization of 10 new monoclonal antibodies against prostate-specific antigen by analysis of affinity, specificity and function in sandwich assays.

While prostate-specific antigen (PSA) is already an invaluable marker for prostate cancer, there is continuing demand for new anti-PSA antibodies with specific characteristics, e.g., high sensitivity and specificity and equimolar binding to free PSA (f-PSA) and the PSA-alpha-1-antichymotrypsin complex (PSA-ACT), as well as the ability to distinguish between these 2 immunoreactive forms of PSA. We have therefore generated and characterized 10 anti-PSA monoclonal antibodies (MAbs). Apparent dissociation constants (Kd) of MAbs were determined by direct ELISA yielding Kd-0.2-164.0 nM. Western blots suggested that 3 of the MAbs (60-1A2, 60-8A2 and 17-1A2) bind to linear epitopes. Sandwich assays identified 5 major antigenic regions as binding targets of the MAbs. Three combinations of MAbs recognize f-PSA and PSA-ACT in equimolar fashion with high sensitivity. Two of the MAb combinations are specific for f-PSA. Physical analysis of the new antibodies has allowed us to assign the MAbs to binding classes (based on their sandwiching capabilities) and to determine accurate apparent dissociation constants.

Animals↗
PubMed1997

Identification of differentially expressed prostate genes: increased expression of transcription factor ETS-2 in prostate cancer.

BACKGROUND: Little is known about the genetic events in the malignant transformation of prostatic cells. This is due in large measure to the cellular heterogeneity of the prostate. METHODS: An amplification method was devised to synthesize cDNA from small samples of cancer and benign tissues of the same resected glands. Differential gene expression of candidate informative markers between cancer and benign was screened by the polymerase chain reaction with gene-specific oligonucleotide primers. RESULTS: The expression of a transcription factor, ETS-2, was shown to be elevated in some cancer specimens. Elevated expression was also noted for neuron-specific enolase (NSE) and another transcription factor, SEF2. CONCLUSIONS: Our method can be used to identify quickly genes that are differentially expressed between benign and cancerous prostate cells. Transcription factors, such as ETS-2, may play a significant role in cancer progression.

Cell Transformation, Neoplastic↗
PubMed1997

Determination of the "reflex range" and appropriate cutpoints for percent free prostate-specific antigen in 413 men referred for prostatic evaluation using the AxSYM system.

OBJECTIVES: Prostate-specific antigen (PSA) exists in the serum in two clinically important molecular forms: free PSA and PSA complexed to alpha 1-antichymotrypsin. Total PSA approximates the sum of the free and complexed forms. Preliminary investigations have illustrated the potential benefits of using percent free PSA to enhance the clinical utility of PSA in distinguishing benign prostate disease from prostate cancer. The current study defines the optimal range of total PSA for measuring percent free PSA (reflex range) and generates appropriate cutpoints for percent free PSA within this range. METHODS: A total of 413 patients, 225 (54%) with benign prostate disease (mean age, 67 years) and 188 (46%) with prostate cancer (mean age, 66 years), who had PSA values between 2.0 and 20.0 ng/mL participated in the investigation. All patients underwent a sextant biopsy to establish the diagnosis. The serum specimens were assayed with the AxSYM PSA assay (total PSA) and AxSYM Free PSA assay (Abbott Laboratories; Abbott Park, IL). Percent free PSA was calculated for all patients. Receiver operating characteristic (ROC) curves were generated for various ranges of total PSA to determine the reflex range that maximized the increase in sensitivity and specificity of percent free PSA over total PSA. Within the optimal range, the ROC curves were utilized to generate cutpoints for percent free PSA to be used in clinical practice. RESULTS: The appropriate reflex range for the utility of percent free PSA was 3.0 to 10.0 ng/mL. The appropriate cutpoint for percent free PSA when the total PSA value was 3.0 to 4.0 ng/mL to achieve 90% sensitivity for the detection of prostate cancer was 0.19. This approach resulted in a biopsy rate of 73% and a cancer detection rate of 44% in men with a total PSA value between 3.0 and 4.0 ng/mL. The appropriate cutpoint for percent free PSA when the total PSA value was 4.1 to 10.0 ng/mL to ensure 95% sensitivity for detection of prostate cancer was 0.24. Within the range of 4.1 to 10.0 ng/mL, this approach resulted in 13% fewer negative biopsies and failure to detect 5% of the cancers. CONCLUSIONS: Percent free PSA should be utilized in patients with a total serum PSA value between 3.0 and 10.0 ng/mL. In patients with a total PSA value between 3.0 and 4.0 ng/mL, percent free PSA enhanced the detection of prostate cancer (improving sensitivity). In patients with a total PSA concentration ranging from 4.1 to 10.0 ng/mL, negative biopsies were eliminated (improving specificity).

Adult↗
PubMed1997

Is partial cystectomy the treatment of choice for mucinous adenocarcinoma of the urachus?

OBJECTIVES: To determine if well-differentiated colonic-type adenocarcinoma of the urachus behaves in a benign fashion, and thus might be treated by segmental rather than radical cystectomy. METHODS: A retrospective review of the literature since 1863 with one added case review is presented here. Only cases with photomicrograph confirmation were accepted. RESULTS: Sixteen previously reported patients with well differentiated colonic-type adenocarcinoma of the urachus were treated by partial cystectomy. None were treated by radical cystectomy. Most (88%) of these patients were cured, whereas all patients (100%) treated in the last 45 years were cured. CONCLUSIONS: These data support a more limited approach to the surgical excision of these benign-appearing tumors. The influence of this histologic type on the prognosis of patients with urachal tumors has not been previously reported.

Adenocarcinoma, Mucinous↗
PubMed1997

Early detection of recurrent prostate cancer with an ultrasensitive chemiluminescent prostate-specific antigen assay.

OBJECTIVES: Treatment failure after radical prostatectomy is most commonly heralded by an increase in serum prostate-specific antigen (PSA) to detectable levels. We evaluated the clinical utility of an ultrasensitive chemiluminescent PSA assay. METHODS: We evaluated the assay in banked sera obtained from 170 men after radical prostatectomy. Controls consisted of 142 females, 29 men who had undergone cystoprostatectomy without evidence of prostate cancer, and 25 men without evidence of recurrent disease at least 5 years after prostatectomy for organ-confined disease. Lead time to diagnosis of recurrence was based on comparisons with the IMx or Tandem E assays using a cutoff of 0.1 ng/mL (100 pg/mL). RESULTS: The biologic level of detection of this assay is 8 pg/mL. Serum PSA levels were undetectable in 82.4% of females, 86.2% of the cystoprostatectomy patients, and 96% of the radical prostatectomy controls. After radical prostatectomy, PSA levels were undetectable at last check in 104 of 168 (61.9%) men. In the 24 men with prostate cancer recurrence, the enhanced sensitivity of 8 pg/mL provided a mean lead time based on conservative calculations of 12.7 to 22.5 months over conventional assays. Thirty-four of the 41 men with detectable PSA levels and no evidence of disease recurrence had PSA levels of 30 pg/mL or less. CONCLUSIONS: PSA levels are undetectable in most men who do not have recurrence of disease after radical prostatectomy. Low but detectable serum PSA levels less than or equal to 30 pg/mL can be produced by nonmalignant sources of PSA. PSA assays with enhanced sensitivity can detect recurrent prostate cancer with significant lead time over conventional assays.

Female↗
PubMed1997

Issues in the assessment of prostate-specific antigen immunoassays. An update.

Prostate-specific antigen (PSA) immunoassays continue to provide unique and valuable information in the early diagnosis and clinical management of prostate cancer. During the past few years there has been considerable progress in the standardization of routine PSA assays and an emergence of PSA assays with novel applications. The authors discuss these developments and provide some insight when assessing the nuances of assay performance and clinical value.

Epitope Mapping↗
PubMed1997

Serum markers as a predictor of response duration and patient survival after hormonal therapy for metastatic carcinoma of the prostate.

PURPOSE: Prostate specific antigen (PSA), prostatic acid phosphatase and alkaline phosphatase were analyzed in 2 large prospective multicenter and multinational trials to assess their correlation with time to progression and overall survival after hormonal therapy for metastatic carcinoma of the prostate. MATERIALS AND METHODS: A total of 868 patients who underwent medical or surgical castration was randomized to receive an oral antiandrogen (nilutamide) or placebo. The serum markers under study were measured at baseline and at 1, 3, 6 and every 6 months thereafter. RESULTS: At baseline the strongest predictive factor was serum alkaline phosphatase. Patients with an alkaline phosphatase of 2 or less times normal lived almost twice as long as those with a level of more than 2 times normal (p < 0.0001). The longer survival was observed in patients whose PSA became normal 3 months after initiation of hormonal therapy compared to those whose PSA never reached normal (p < 0.0001). CONCLUSIONS: Serum markers at baseline and during the few months after initiation of hormonal therapy can provide prognostic information for the clinical treatment of patients with metastatic carcinoma of the prostate. In addition, the PSA level at month 3 can serve as a surrogate end point in clinical trials.

Acid Phosphatase↗
PubMed1997

[In vitro and in vivo models developed from human prostatic cancer].

The possibility of maintaining and studying human prostatic cancers in an in vitro and in vivo environment has allowed the development of rare but essential tools to study many aspects of the biology of these cancers. Although none of the available models is perfect, the sum of the studies conducted with these models over more than 20 years constitutes the basis for major progress in our understanding of this disease. The most widely used cell lines (cultured in vitro) are PC-3, DU-145 and LNCaP. They are limited by the fact that they are essentially androgen-independent cell lines, derived from metastatic sites. Due to the slow growth of prostatic cancers, it is very difficult to obtain cancer cell lines which can be transplanted in immunodeficient animals (such as athymic mice) and only a few xenografts are currently available, some of which, like PCV-82, LuCaP 23, CWR-22, are androgen-dependent or sensitive. These models can be used to study host-tumour interactions as well as endocrinological interactions, stroma-tumour cell interactions, and to analyse molecular phenomena related to stages of hormone dependence and hormone resistance. In vitro and in vivo models of metastatic prostatic cancer have also been developed and appear to have a crucial impact on the understanding of metastatic mechanisms and new therapeutic approaches. This paper describes the main experimental models developed from human prostatic cancers, their main characteristics, their value compared to clinical cancers and some of the major studies conducted with these models. Due to the exponential progress in molecular biology techniques and oncogenetics, it appears essential to increase the number and diversity of experimental models of prostatic cancer in order to advance research concerning the crucial phenomena occurring during the course of this disease, from oncogenesis to currently incurable metastatic stages.

Androgens↗
PubMed1996

Cell proliferation and apoptosis during prostatic tumor xenograft involution and regrowth after castration.

The biological mechanisms involved in androgen-dependent and -independent prostate cancer growth after castration were analyzed in the LuCaP 23.1 human prostate cancer xenograft model. Athymic mice (n = 82) bearing LuCaP 23.1 xenograft were castrated and tumors were harvested at different time points from day 0 to day 112 post castration. In each group of mice, tumor growth rate (TGR), serum PSA concentration, percentage of tumor cells incorporating bromodeoxyuridine (BUdR index), percentage of apoptotic tumor cells assessed by morphological analysis (apoptotic index), and presence of apoptosis-related DNA "ladder" were analyzed. Castration induced a significant decrease in TGR and serum PSA from day 1 to day 7, and a progressive increase in the 2 parameters from day 14 to day 112, heralding androgen-independent tumor relapse. Meanwhile the BUdR and apoptotic indexes varied as follows after castration: an increase was noted for both at day 3, a significant increase in apoptotic index with a decrease in BUdR index from day 5 to day 14, and a progressive decrease in apoptotic index while BUdR index remained at 50% of the pre-castration value from day 28 to day 112. DNA ladder was present sparsely in tumors grown in non-castrated hosts, universally present in tumors from day 1 to day 28 post castration, and frequent in tumors from day 56 to 112. Castration-induced effects in LuCaP 23.1 tumors were characterized by an increase in number of apoptotic cells and a decrease in proliferative activity. The androgen-independent tumor relapse after castration was associated with a low apoptotic index with no increase in proliferative activity.

Animals↗
PubMed1996

Prostatic cell lineage markers: emergence of BCL2+ cells of human prostate cancer xenograft LuCaP 23 following castration.

A model of prostate cancer progression based on the expression pattern of informative genes in the human prostate cancer xenograft LuCaP 23.1 is presented. Apparently, there are at least 2 tumor cell populations of LuCaP 23.1, representing 2 different phenotypes. One is NSE (neuron-specific enolase)-positive and the other NSE-negative. NSE-positive tumors were recovered after hormone-independent growth in castrated mice. These hormone-independent tumors also expressed BCL2, a gene product shown to inhibit apoptosis. With NSE, BCL2 and PSA (prostate-specific antigen) as identifying markers, the model specifies a putative progression sequence of the prostate cancer cell types. We also show a proposed lineage relationship among the 3 principal normal cell types found in the prostatic epithelium.

Animals↗
PubMed1996

Intermittent androgen suppression delays progression to androgen-independent regulation of prostate-specific antigen gene in the LNCaP prostate tumour model.

In most patients with prostate cancer, continuous androgen suppression (CAS) therapy causes tumour regression and an accompanying decrease in serum prostate specific antigen (PSA). However, with tumour progression, regulation of both tumour growth and PSA gene expression becomes androgen-independent. Because androgen resistance develops, in part, from adaptive cell survival mechanisms activated by androgen withdrawal, we hypothesize that intermittent re-exposure to androgens may prolong time to androgen-independent progression. The objective of this study was to determine whether intermittent androgen suppression (IAS) could delay the onset of androgen-independent PSA gene regulation in LNCaP prostate tumour model when compared to CAS. Five or six cycles of IAS were possible before progression developed. IAS prolonged time to androgen-independent PSA gene regulation from an average of 26 days in CAS to 77 days in IAS. Serum PSA increased above pre-castrate levels in all mice treated with CAS by 28 days post-castration, but remained below pre-castrate levels in 75% of IAS-treated mice by 60 days post-castration. By 15 weeks post-castration, serum PSA levels increased 7-fold above pre-castrate levels in CAS-treated mice compared to 1.9-fold increase in IAS-treated mice. PSA mRNA expression levels highly correlated with serum PSA levels in both groups. Maintenance of androgen dependency through IAS may be due to androgen-induced differentiation and/or down-regulation of androgen-suppressed gene expression.

Androgens↗
PubMed1996

Intermittent androgen suppression with leuprolide and flutamide for prostate cancer: a pilot study.

OBJECTIVES: To affirm the feasibility of using intermittent androgen suppression in patients with hormone-naive prostate cancer. METHODS: Leuprolide and flutamide were administered for 9 to 12 months and then discontinued until prostate-specific antigen (PSA) levels reached a threshold value determined by the baseline PSA value. This constituted one cycle of treatment. Androgen suppression was then administered intermittently as described until there was evidence of androgen independence. RESULTS: Twenty-two patients with PSA failure after primary therapy with surgery and/or radiation and untreated early or Stage D2 disease were treated. Twenty-one patients completed androgen suppression during cycle 1, with a median time to PSA nadir of 3.5 months (range, 2 to 12). Fifteen patients completed cycle 1 with a median time off treatment of 6 months (range, 2 to 19) or 38% (range, 17% to 64%) of a treatment cycle. Six patients continued off treatment during cycle 1 for 1+ to 31+ months. During cycle 2, 12 patients achieved a PSA nadir in a median time of 3.5 months. Two patients completed cycle 2 with a median time off treatment of 10 months (51%). Median follow-up for all patients is 26 months (range, 10 to 51). While off treatment, all patients reported a reduction of symptoms associated with androgen suppression. CONCLUSIONS: Intermittent androgen suppression is a feasible alternative to continuous androgen suppression for treatment of prostate cancer, and quality of life is improved while off treatment.

Aged↗
PubMed1996

Urinary nuclear matrix protein as a marker for transitional cell carcinoma of the urinary tract.

PURPOSE: The purpose of this trial was to evaluate an immunoassay for urinary nuclear matrix protein, NMP22, as an indicator for transitional cell carcinoma of the urinary tract. MATERIALS AND METHODS: Three groups of subjects participated in this trial of NMP22: 1-175 with transitional cell carcinoma, 2-117 with benign urinary tract conditions and 3-375 healthy volunteers. Each subject provided a single (3 voids) urine sample for analysis at the time of study entry. Each sample was assayed for the level of NMP22. RESULTS: In normal healthy volunteers and in subjects with benign conditions median NMP22 levels were 2.9 and 3.3 units per ml., respectively. Median urinary NMP22 levels in patients with transitional cell carcinoma were significantly greater than in comparison subjects. Patients with active transitional cell carcinoma had significantly greater median urinary NMP22 levels than those with no evidence of disease (6.04 versus 4.11 units per ml., p = 0.027, 1-tailed Mann-Whitney U test). We noted no effect of tumor grade, extent of disease or exposure to intravesical therapy on urinary NMP22 levels. CONCLUSIONS: NMP22 is a promising urinary tumor marker for monitoring transitional cell carcinoma. Nuclear matrix proteins are a new class of tumor markers that represent the basis for the development of assays with increased efficacy for the detection and treatment of cancer.

Aged↗
PubMed1996

Preclinical models of prostate cancer.

Prostate cancer is the most common non-skin malignancy, yet the biological and molecular characteristics of the disease remain only poorly understood. One of the many reasons for this is that there are so few animal or human laboratory models of prostate cancer. Prostate cancer rarely arises spontaneously in animals, and the human cancer is unusually hard to grow in culture or as xenografts even short-term. The prostate cancer models that do exist are basically rodent models, human cell lines, human xenografts, and gene transfer and transgenic models. Many laboratories have put great effort into developing prostate cancer models, without much success. These efforts recently have been forced to be curtailed, primarily due to a lack of funding. There is good reason to believe, however, that propagation of metastatic tissue will be much more successful. At the University of Washington, the Prostate Cancer Donor Program, organized in a manner similar to existing methods for cadaver organ harvest, has been instituted to help recruit patients for these approaches. Prospects for success of model development also have been improved because of advances in techniques for the maintenance of severe combined immunodeficiency disease mice or nude mice.

Animals↗