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N L Block

Publications and source records attributed to N L Block.

At least 19 recordsLinked to original sources
PubMed1996

Modulation of aromatase activity by growth factors in an androgen sensitive human prostate cancer cell line, LNCaP.

The effects of steroids and peptide growth factors on aromatase activity in an androgen sensitive human prostate cancer cell line (LNCaP) were investigated. Factors were selected based on their observed modulation of the enzyme in other tissues. Incubation with epidermal growth factor and transforming growth factor-I decreased aromatase activity in LNCaP cells by 25-40%. Insulin like growth factor-1, dexamethasone, dibutyryl cAMP and phorbol 12-myristate 13-acetate, all of which are modulators of aromatase in other tissues, had no significant effect on aromatase activity in LNCaP cells. In addition, the cAMP-dependent protein kinase and protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2 methylpiperazine (H-7) had no effect on the enzyme activity. Factors affecting prostatic aromatase may be distinct from those for other known species.

Androgens↗
PubMed1996

Inhibition of aromatase activity and growth suppression by 4-methoxy-4-androstene-3,17-dione in an androgen sensitive human prostatic carcinoma cell line.

Aromatization of testosterone to estradiol was investigated in a human prostatic carcinoma cell line, LNCaP. A saturable, dose and time-dependent aromatization of testosterone was observed. Kinetic parameters, Km (201 nM) and V(max) (0.76 pmol/h) per mg) and also the inhibition constants (Ki) for various aromatase inhibitors were calculated from standard Lineweaver-Burke plots. The steroidal aromatase inhibitor 4-hydroxy-4-androstene-3,17-dione (4-OHA) and its derivative, 4-methoxy-4-androstene-3,17-dione (4-OMA), inhibited aromatization of testosterone in a competitive pattern of inhibition. The derivative 4-OMA is the stronger inhibitor of the two, with an apparent Ki of 1.12 microM, whereas the apparent Ki of 4-OHA is 3.28 microM. Long term incubation with 4-OMA suppressed proliferative activity of LNCaP cells in the presence of physiological levels of testosterone (10(-10) M to 10(-7) M). In contrast, 4-OHA was a growth promoter. These results suggest a potential role for aromatase in hormone responsive prostate cancer.

Androstenedione↗
PubMed1996

Association of elevated levels of hyaluronidase, a matrix-degrading enzyme, with prostate cancer progression.

Components of extracellular matrix and the matrix-degrading enzymes are some of the key regulators of tumor metastasis and angiogenesis. Hyaluronic acid (HA), a matrix glycosaminoglycan, is known to promote tumor cell adhesion and migration, and its small fragments are angiogenic. We have compared levels of hyaluronidase, an enzyme that degrades HA, in normal adult prostate (NAP), benign prostate hyperplasia (BPH) and prostate cancer (CaP) tissues and in conditioned media from epithelial explant cultures, using a sensitive substrate(HA)-gel assay and an ELISA-like assay. The results show a significant elevation (3-10-fold) of this enzyme in tumor tissues compared to that in NAP and BPH tissues. Furthermore, the hyaluronidase levels in tissues correlates well with the tumor grade. For example, the concentrations in a locally extended CaP lesion (191 +/- 7.9 milliunits/mg protein), and low-grade tumors (9.4 +/- 1.4 milliunits/mg protein), respectively. Among the primary epithelial explant cultures, CaP cultures secrete at least 10-fold higher levels of hyaluronidase that those secreted by NAP and BPH cultures. Furthermore, among the established prostate cancer cell lines, DU145, an androgen-unresponsive metastatic line, secretes 4-fold more hyaluronidase than LNCaP, an androgen-responsive and relatively well-differentiated cell line. We also show that prostatic hyaluronidase has an apparent M(r) approximate to 55,000, a pH optimum of 4.6, and is distinct from other well-characterized hyaluronidases.

Adult↗
PubMed1996

Radical prostatectomy: is complete resection of the seminal vesicles really necessary?

PURPOSE: We determined the frequency of prostate cancer extension into the distal 1 cm. of seminal vesicles, and reconsidered whether complete excision of the seminal vesicles during radical prostatectomy is always necessary. MATERIAL AND METHODS: After en bloc removal with the specimen in 71 consecutive radical prostatectomies, the distal 1 cm. of each seminal vesicle was transected and separately analyzed for tumor involvement. RESULTS: Mean patient age was 61.8 years (range 40 to 72). Preoperative prostate specific antigen (PSA) ranged from 0.8 to 37 ng./dl. (median 7.3), and 18 patients had a PSA of 10 or more. Clinical stages were T1b in 1 case T1c in 37, T2a in 12, T2b in 10, T2c in 6 and T3a in 1. Preoperative Gleason sums ranged from 4 to 8 (median 6) with 21 patients (30%) having a sum of 7 or more. Of 71 patients 12 (17%) and seminal vesicle invasion (5 bilaterally). In no case did tumor extend into the distal 1 cm. of the seminal vesicle. PSA at diagnosis ranged from 4.2 to 30 ng./dl., with 4 of 12 patients having a PSA of 10 or more. Preoperative clinical stages were T1c in 5 cases, T2a in 3, T2b in 2 and T2c in 2. Five of the 12 patients (42%) had positive surgical margins and 11 (92%) had a postoperative Gleason sum of 7 or more. CONCLUSIONS: In 71 consecutive patients undergoing radical prostatectomy no tumor was found in the distal 1 cm. of the seminal vesicles, including 12 with seminal vesicle invasion. We continue to advocate complete excision of the seminal vesicles during radical prostatectomy. However, if dissection is difficult and a small fragment is left behind, the prognosis is unlikely to be altered.

Adult↗
PubMed1995

Goserelin versus orchiectomy in the treatment of advanced prostate cancer: final results of a randomized trial. Zoladex Prostate Study Group.

OBJECTIVES: To compare the efficacy and safety of goserelin and orchiectomy in patients with stage D2 prostate cancer. METHODS: A randomized, open, multicenter study was conducted in 283 patients. Patients were allocated to goserelin, 3.6 mg every 28 days or to orchiectomy. Study end points were endocrine response, objective response, time to treatment failure, survival, and tolerability. Objective response was based on modified criteria of the National Prostate Cancer Project. RESULTS: Serum testosterone decreased from baseline to castrate levels by week 4 in each group and remained below castrate levels thereafter. Acid phosphatase and alkaline phosphatase concentrations also decreased in each group. The goserelin and orchiectomy groups had similar results for objective response (82% versus 77%) and had similar medial times to treatment failure (52 versus 53 weeks) and survival (119 versus 136 weeks). No significant interactions between treatments and prognostic factors were observed. Adjusting for baseline testosterone concentration had no effect on survival outcome. Race had no influence on outcome or efficacy end points. Common adverse events in both groups were pain, hot flushes, and lower urinary tract symptoms. CONCLUSIONS: Goserelin is well tolerated and as effective as orchiectomy in patients with Stage D2 prostate cancer.

Aged↗
PubMed1995

Single-agent therapy with bicalutamide: a comparison with medical or surgical castration in the treatment of advanced prostate carcinoma.

OBJECTIVES: Single-agent therapy with bicalutamide, a nonsteroidal antiandrogen, was compared with castration, either surgical or medical, in patients with untreated Stage D2 prostate cancer. METHODS: In an open, randomized, multicenter trial, patients were randomized to treatment with 50 mg bicalutamide (n = 243) once daily or to castration (n = 243), either orchiectomy or depot injection of goserelin acetate every 28 days. Primary efficacy endpoints were times to treatment failure and objective disease progression and survival. Assessments included review of measurable metastases, prostate dimensions, Eastern Cooperative Oncology Group performance status, pain, analgesic requirements, and quality of life responses. RESULTS: The median duration of therapy was 39 weeks for bicalutamide-treated patients and 42 weeks for castrated patients; treatment failure occurred in 53% and 42% and disease progression in 43% and 33%, respectively. Treatment effects favored castration for both endpoints (P < or = 0.002), with hazard ratios (bicalutamide:castration) of 1.54 (95% confidence interval [CI], 1.18 to 2.00) for time to treatment failure and 1.6 (95% CI, 1.19 to 2.15) for time to disease progression. From the 1-year survival analysis, the hazard ratio for probability of death was 1.29 (95% CI, 0.96 to 1.72). Thus far, with a median follow-up of 86 weeks, median survival has not been reached in either group. Changes from baseline in several quality of life variables were significantly different (P < or = 0.01) between treatment groups periodically from months 1 to 6, and all favored bicalutamide. Overall, the antiandrogen was well tolerated compared with castration; with bicalutamide, hot flushes occurred less often and breast tenderness and gynecomastia more often. CONCLUSIONS: Although a dosage of 50 mg of bicalutamide once daily was not as effective as castration, the favorable quality of life outcomes and the low incidence of nonhormonal adverse events provide reasons to evaluate bicalutamide, as a single therapeutic agent, at higher doses.

Aged↗
PubMed1995

Flow-cytometric DNA analysis of paraffin-embedded renal cell carcinoma tissue from patients treated by parenchymal-sparing surgery.

OBJECTIVE: To determine the utility of deoxyribonucleic acid (DNA) ploidy pattern, detected by flow cytometry, in predicting the outcome of renal cell carcinoma (RCC). PATIENTS AND METHODS: DNA content was retrospectively assessed by flow cytometry in 28 primary paraffin-embedded RCCs from 24 patients (16 men and eight women, mean age 61.9 years, range 40-89) who had undergone renal parenchymal-sparing surgery. RESULTS: Tumour recurred locally in three patients, two with diploid tumours and one with aneuploid tumour. Two patients with diploid tumours had metastatic disease 11-58 months after surgery. Only one patient with aneuploid tumour developed metastatic disease. There was no difference in local recurrence or metastases with the type of renal parenchymal-sparing surgery used (enucleation or partial nephrectomy) nor any significant difference in overall survival (P = 0.11). CONCLUSION: While DNA content might be of considerable predictive value for patients with RCC, these results showed that there was no difference in mortality rate, recurrence rate, or type of renal parenchymal-sparing surgery used between aneuploid and diploid tumours.

Adult↗
PubMed1995

Conservative surgical treatment of renal cell carcinoma. The University of Miami experience.

Thirty-four patients with renal cell carcinoma underwent renal parenchymal-sparing surgery; 10 enucleation (Group A), 15 partial nephrectomy (Group B), and nine a combination of procedures (Group C). Conservative surgery was performed in the presence of normal contralateral unit in four patients (11.7%). Local recurrence (group A = 1, group B = 2, group C = 2) developed in five patients. Metastases appeared in six patients (17.6%) from 12 to 58 months postoperatively. Adequate renal function was obtained in 32 of the 34 patients. Mean follow-up for all patients was 64.6 months overall, 75.6 months from group A, 64.1 months for group B and 53.4 months for group C. The three and five year probabilities of survival for all patients were 77.8% and 69.5% respectively, 80% for group A, 80% for group B and 85% and 57.1% for group C. Enucleation and partial nephrectomy are both viable options in the management of solitary or bilateral renal cell carcinoma. There is no decline ineffective tumor control and prognosis.

Actuarial Analysis↗
PubMed1994

Enhancement of hyperthermic toxicity by lonidamine in the Dunning R3327G rat prostatic adenocarcinoma.

Hyperthermia alone or with radiation is used therapeutically for localized solid tumors. Clinical experience shows that sustained tumor temperature exceeding 45 degrees C damages normal tissue. Any agent that enhances the effects of hyperthermia at or below this temperature may have clinical relevance. Lonidamine and hyperthermia were tested on the Dunning R3327G rat prostatic adenocarcinoma. Using colony-formation assays, cytotoxic effects of each agent alone and in combination were quantified. Lonidamine to 100 micrograms/ml was not significantly toxic, but in combination, it enhanced cytotoxicity. Survival patterns after fractionated hyperthermia revealed a rapid development and decay of thermotolerance. Measurement of cell-cycle progression following a single dose of hyperthermia revealed a reduction of S-phase cells, and subsequent accumulation in G1 over 24 hours. Combination treatment of tumor-bearing rats significantly reduced tumor growth rate when compared with individual agents. These results suggest a potential use of lonidamine in hyperthermic therapy of prostate tumors.

Adenocarcinoma↗
PubMed1994

Detection of prostatic-inhibin-like peptide in the cytoplasm of LNCaP cells, a human prostatic adenocarcinoma cell line.

Prostatic inhibin peptide (PIP) is a 94-amino acid peptide involved in various cellular functions. The concentration of this peptide changes with prostatic pathophysiology suggesting a role in various disease conditions; present study was undertaken to investigate the presence of this peptide in two human prostatic cell lines: LNCaP and PC3 cells. The LNCaP cells showed an intense intracellular fluorescence pattern after staining with rabbit-anti-PIP antiserum and FITC conjugated goat antirabbit-IgG, while the PC3 cells did not exhibit any fluorescence. There was no alteration in the concentration of PIP in LNCaP cells with or without supplementation of steroids in culture medium. Immunoblot analysis indicates similarities between PIP from LNCaP cells and that from the human seminal plasma. Thus, present study demonstrates the presence of PIP in a human prostatic cell line, i.e., LNCaP cells. Its intracellular concentration is androgen independent, and has a close similarity with PIP isolated from the human seminal plasma.

Adenocarcinoma↗
PubMed1994

Identification of the human seminal TRH-like peptide pGlu-Phe-Pro-NH2 in normal human prostate.

Human and rat prostate contain thyrotropin-releasing hormone immunoreactivity (iTRH) including TRH and an uncharged TRH-like peptide. Recently the uncharged TRH-like peptide pGlu-Phe-Pro-NH2 was purified from human semen. To determine whether this peptide was of prostatic origin, human and rat prostate extracts were analyzed by ion-exchange chromatography and reversed-phase HPLC. The predominant uncharged iTRH comigrated exactly with synthetic pGlu-Phe-Pro-NH2 on HPLC and had identical affinity to pGlu-Phe-Pro-NH2 in a TRH radioimmunoassay. We conclude that prostate is a source of this peptide in humans and rats. This amidated TRH-like peptide may play a role in human reproductive physiology.

Adolescent↗
PubMed1994

Renal parenchyma-sparing surgery as conservative treatment of renal cell carcinoma.

OBJECTIVE: To evaluate the role of parenchyma-sparing surgery in patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: Between 1965 and 1990, 34 patients with RCC underwent renal parenchyma-sparing surgery. There were 22 men and 12 women with a mean age of 62 years (range 40-89). Ten patients underwent enucleation (Group A), 15 partial nephrectomy (Group B), and nine a combination of procedures (Group C). Conservative surgery was performed in the presence of a normal contralateral unit in four patients (12%). RESULTS: Five patients developed local recurrence. Metastases appeared in six patients (18%) from 12 to 58 months post-operatively. Adequate renal function was obtained in 32 of the 34 patients. The mean follow-up for all patients was 64.6 months overall, 75.6 months for group A, 64.1 months for group B and 53.4 months for group C. The 3 and 5 year probabilities of survival for all patients were 77.8% and 69.5% respectively. The probabilities of 3 and 5 year survival were 80% for group A, 80% for group B and 71.4% and 57.1% for group C. CONCLUSION: Enucleation and partial nephrectomy are both viable options in the management of solitary or bilateral RCC, as there is no decline in effective tumour control and prognosis. Larger groups and longer follow-ups are needed to assess the role of renal parenchyma-sparing surgery more definitively.

Adult↗
PubMed1993

Human prostatic inhibin suppresses tumor growth and inhibits clonogenic cell survival of a model prostatic adenocarcinoma, the Dunning R3327G rat tumor.

Prostatic inhibin (PI) is a M(r) 10,700 protein found in human seminal plasma and is secreted by the prostate. Recognition of alteration of PI levels in prostatic diseases prompted us to investigate its effect on an animal prostatic adenocarcinoma model, the Dunning R3327G rat tumor. PI not only inhibited in vitro growth of tumor cells but also suppressed tumor growth in vivo. A dose-dependent inhibition of both the clonogenic cell growth and rate of proliferation (DNA synthesis) was observed in tumor cell cultures incubated with purified PI. These inhibitory activities were similar in both androgen-dependent and androgen-independent Dunning tumor cell lines. A functional decapeptide of PI was also found to inhibit Dunning tumor cell colonies in a dose-dependent manner. Daily injection of purified PI into tumor-bearing rats suppressed the tumor growth. A 58% reduction in tumor weight and a 2-fold reduction in tumor growth rate were observed over a 15-day treatment period. Continued treatment with PI significantly suppressed the tumor growth rate by nearly 3-fold. These findings clearly demonstrate a potential application of PI for treating human prostatic adenocarcinoma.

Adenocarcinoma↗
PubMed1993

Secretion of matrix metalloproteinases and their inhibitors (tissue inhibitor of metalloproteinases) by human prostate in explant cultures: reduced tissue inhibitor of metalloproteinase secretion by malignant tissues.

Unregulated secretion of matrix metalloproteinases (MMPs) or their endogenous protein inhibitors (tissue inhibitor of metalloproteinases, TIMPs) has been implicated in tumor invasion and metastasis. Species of MMPs and TIMPs secreted by epithelial cultures of normal, benign, and malignant prostate were identified and their levels were compared. Fragments of fresh tissue were cultured in a serum-free medium that supported the outgrowth of prostatic epithelial cells. Biochemical analysis of the conditioned media by gelatin zymography and enzyme assays showed that both normal and neoplastic tissues secreted latent and active forms of both M(r) 72,000 type IV collagenase (MMP-2) and M(r) 92,000 gelatinase (MMP-9). However, conditioned media from malignant prostate explants contained a higher proportion of the active form of MMP-2. Significant amounts of free TIMPs were secreted by normal juvenile and adult prostates, but they were either markedly reduced or not detectable in conditioned media from neoplastic tissues. These findings suggest that there is an imbalance of secretion between MMPs and TIMPs in prostatic carcinoma.

Adult↗
PubMed1993

Flow cytometric analysis of DNA and nuclear protein in paraffin-embedded tissue.

Previously we described the simultaneous quantification of DNA and nuclear protein in unfixed tissue from solid tumors. The resultant 2 parameter flow cytometric analysis has several advantages over that of DNA alone. In this report, we describe a modification of the technique for the analysis of formalin-fixed paraffin-embedded tissue. Paraffin-embedded material was prepared by hydrating sections, incubating in 0.5% pepsin solution, washing, and resuspending in buffer containing nonionic detergent. The nuclei were then stained with fluorescein isothiocyanate and propidium iodide in the presence of ribonuclease. Several solid tumor tissue types have been analyzed, including breast, colon, kidney, and thymus. The best results were obtained when the initial pepsin treatment was for 1.5 h, instead of 0.5 h. Pepsin treatment for 1.5 h improved the CVs of both the DNA and nuclear protein parameters, and did not appear to reduce nuclear protein levels or to cause significant disintegration of nuclei. The DNA/nuclear protein histograms of unfixed and fixed, paraffin-embedded tissue were similar. Since tumor nuclei typically have higher protein levels than DNA-diploid nuclei, the technique reduces population overlapping and permits less subjective identification of DNA aneuploidy.

Aneuploidy↗
PubMed1993

Recognition and reduction of artifacts from autolysis in paraffin-embedded tissue using DNA/nuclear protein flow cytometry.

Artifacts from autolysis can be a problem in retrospective flow-cytometric analyses of DNA content in paraffin-embedded tissues. Autolyzed tissue from rat liver, human liver, and rat spleen were stained for DNA and nuclear protein to determine if this technique would be useful in identifying partially degraded cells. After the tissue was deparaffinized and rehydrated, the nuclei were isolated using 0.5% pepsin. Propidium iodide (PI) and fluorescein isothiocyanate (FITC) were used to stain DNA and nuclear protein. When unfixed rat liver tissue was allowed to undergo autolysis at 4 degrees C for 24-48 h before fixation, there was a progressive broadening of the G1 and G2M DNA peaks and a slight increase in the average DNA contents of these peaks. Nuclei that stained more intensely with PI also stained more intensely with FITC. Similar results were obtained using human liver and rat spleen. Sometimes the increased PI staining resulted in a false aneuploid peak. The distinctive skewing of the DNA/nuclear protein histograms from autolysis was reduced by increasing the incubation of the tissue in 0.5% pepsin from 0.5 h to 1.5 h during the nuclei-isolation step. The DNA/nuclear protein method provides a means for identifying artifacts from autolysis, whereas the extended pepsin treatment provides a means for reducing these artifacts.

Animals↗