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Biomedical subjects

J B Nelson

Publications and source records attributed to J B Nelson.

At least 19 recordsLinked to original sources
PubMed2001

Increased fatty acid synthase as a therapeutic target in androgen-independent prostate cancer progression.

BACKGROUND: Fatty acid synthase (FAS) performs the anabolic conversion of dietary carbohydrate or protein to fat. FAS expression is low in most normal tissues, but is elevated in many human cancers, including androgen-sensitive and androgen-independent prostate cancer. METHODS: Immunohistochemical evaluation of FAS expression was performed in human prostate cancer specimens under various states of androgen ablation. In vitro and in vivo prostate cancer models were evaluated for FAS expression and activity under androgenic and androgen-depleted conditions, and were tested for sensitivity to antimetabolite drugs that target fatty acid synthesis. RESULTS: While FAS expression in the prostate was androgen responsive, it persisted or was reactivated in human prostate carcinoma after androgen ablation, and was high in 82% of lethal tumors examined at autopsy. Similar patterns of FAS expression and fatty acid synthesis were seen in cell culture and xenograft models of human prostate cancer. Pharmacologic inhibition of FAS resulted in a dose-dependent reduction of tumor growth in these models, including fourfold inhibition of an androgen-independent human prostate cancer xenograft with little associated toxicity. CONCLUSIONS: The data suggest that FAS expression/FA synthesis provides an important functional aspect of the malignant phenotype in prostate cancer, perhaps supporting cell growth or survival. FAS expression may be upregulated by alternate signaling pathways important for prostate cancer growth under androgen withdrawal. The re-emergence of FAS expression and activity during the development of androgen independence demonstrate that FAS may serve as a novel target for antimetabolite therapy in prostate cancer.

4-Butyrolactone↗
PubMed2001

Detection of increased choline compounds with proton nuclear magnetic resonance spectroscopy subsequent to malignant transformation of human prostatic epithelial cells.

In this study, a panel of normal human prostate cells (HPCs) and tumor cells derived from metastases were studied by (1)H NMR spectroscopy to determine whether the malignant transformation of HPCs results in the elevation of choline compounds. Although an elevated choline signal has been observed previously in clinical studies, the contribution of the different Cho compounds to this elevation, as well as their quantification, has not been established until now. Here we have shown that HPCs derived from metastases exhibit significantly higher phosphocholine as well as glycerophosphocholine levels compared with normal prostate epithelial and stromal cells. Thus the elevation of the choline peak observed clinically in prostate cancer is attributable to an alteration of phospholipid metabolism and not simply to increased cell density, doubling time, or other nonspecific effects. Androgen deprivation of the androgen receptor-positive cell lines resulted in a significant increase of choline compounds after chronic androgen deprivation of the LNCaP cell line and in a decrease of choline compounds after a more acute androgen deprivation of the LAPC-4 cell line. These data strongly support the use of proton magnetic resonance spectroscopic imaging to detect the presence of prostate cancer for diagnosis, to detect response subsequent to androgen ablation therapy, and to detect recurrence.

Androgens↗
PubMed2001

Nonandrogenic mediators of prostatic growth.

Prostate growth and development are primarily under the control of androgens; however, other factors can also influence prostatic growth through alternative pathways. This article discusses some of the major nonandrogenic mediators of prostate growth. Information on the pathways by which these factors exert their effects is also reviewed.

APUD Cells↗
PubMed2000

Endothelium-derived factors as paracrine mediators of prostate cancer progression.

BACKGROUND: Vascular endothelium represents a complex network of cells producing a large number of active substrates affecting physiologic, metabolic, and immunologic properties of the whole organism, as well as particular organs or tissues. The potential influence of endothelium-derived paracrine factors on prostate cancer progression has only begun to be examined. METHODS: This review summarizes recent literature on endothelium-derived factors, including vasoactive agents, peptide growth factors, cytokines, and colony-stimulating factors, involved in the development and progression of prostate cancer. RESULTS: Endothelial cells produce an array of active substrates, many of which have been shown to influence prostate cancer growth. Available data demonstrate the positive impact of such molecules as endothelin-1, basic FGF, TGF-beta, IL-6, and IL-8 on prostate cancer progression. Many other endothelium-derived factors NO, IGF, PDGF, IL-1, G-CSF, and GM-CSF (Nitric Oxide, Insulin-Like Growth Factor, Platelet-Derived Growth Factor, Interleukin-1, Granulocyte Colony Stimulating Factor, and Granulocyte-Macrophage Colony Stimulating Factor) are, at best, implicated in prostate cancer growth, and in most cases support cancer progression. CONCLUSIONS: A better understanding of endothelium-derived factors, as paracrine mediators of prostate carcinogenesis and progression, should aid in the development of novel therapeutic strategies.

Cell Division↗
PubMed2000

Evaluation of the effect of spinal cord injury on serum PSA levels.

OBJECTIVES: Prostatic structure and secretory activity are thought to be influenced by autonomic innervation of the prostate. Prostatic denervation is especially likely in patients with spinal cord injury (SCI) at the level of the cauda equina or the conus medullaris, where the peripheral nerve supply to the prostate may be specifically damaged. This may result in changes in serum prostate-specific antigen (PSA) levels, either directly or indirectly. Therefore, we measured serum PSA levels and also studied the influence of factors such as age, catheterization, duration of SCI, urinary tract infection, and history of cystitis on serum PSA values in men with SCI. METHODS: Serum PSA levels were determined in 79 men with SCI (age older than 40 years) using banked sera by the Abbott MEIA PSA assay. Variables such as age, catheterization, duration of SCI, urine culture results, and history of cystitis were obtained from a review of patient records. Comparisons were made with a randomly selected, non-SCI control population of 501 men, 40 to 89 years old, who underwent serum PSA determination at our institution. Statistical comparisons were performed using the Mann-Whitney U test (nonparametric), since the populations were not normally distributed. Multivariate logistic regression analysis was used to assess the correlation between the various factors and the serum PSA levels in men with SCI. RESULTS: No statistically significant differences were found in the median serum PSA values between the SCI group and the non-SCI control population. The age-specific PSA values obtained in the SCI group were also comparable to those reported for the general population at large. Age (P <0.03) and the presence of a catheter (P <0.0002) were the only two factors that were correlated with higher serum PSA values in the SCI group by regression analysis. CONCLUSIONS: Men with SCI tended to have serum PSA value distributions that were similar to those of the general population. However, those in the SCI group who had indwelling catheters were more likely to have higher PSA values at baseline, as were older men with SCI.

Adult↗
PubMed2000

Non-steroidal anti-androgens in prostate cancer--current treatment practice.

Adenocarcinoma of the prostate is a common disease that causes significant morbidity and mortality in the adult male population. Hormonal therapy for prostate cancer is considered when a patient fails with initial curative therapy, such as radical prostatectomy or definitive radiation therapy, or if he is found with an advanced disease. Many hormonal agents have been developed to exploit the fact that prostate cancer growth is dependent on androgen. Non-steroidal anti-androgens (NSAAs) block androgen at the cellular level. Numerous clinical trials comparing monotherapy of castration and combination therapy of castration and NSAAs have been performed. At present, the results of the trials with regard to the survival of patients under therapy are conflicting. When the disease recurs in a patient in the middle of combination androgen blockade therapy, androgen withdrawal should be considered. The benefits of NSAA in monotherapy, intermittent or neoadjuvant therapy are not clear at present. Better designed, larger cohort clinical trial may be necessary to clarify the confusion.

Calcium Oxalate↗
PubMed2000

Methylation of the neutral endopeptidase gene promoter in human prostate cancers.

Neutral endopeptidase 24.11 (NEP) is a cell surface peptidase expressed by prostatic epithelial cells that cleaves and inactivates neuropeptide growth factors implicated in the growth of androgen-independent prostate cancer (PC). Decreased NEP expression in hormone-refractory metastatic PCs can result from hormonal therapies because NEP transcription is induced by androgens and down-regulated by androgen withdrawal. NEP is encoded by a gene that contains a 5' CpG island spanning a transcriptional regulatory region. In this study, we investigate whether DNA hypermethylation of the NEP promoter accompanies decreased NEP expression in PC cell lines and whether it occurs in human PC tissues in vivo. DNA isolated from PC cell lines and from normal and neoplastic human prostate tissues was restriction-digested with a methylation-sensitive restriction endonuclease and analyzed by Southern blot using a 5' sequence-specific NEP probe. Methylation-specific PCR was performed using PCR primers designed to discriminate between methylated and unmethylated alleles, and reverse transcription-PCR using NEP-specific primers was performed on cDNA extracted from PC cells treated with 5-aza-2'-deoxycytidine. Methylation of the NEP promoter was present in androgen-independent PC cell lines but not in androgen-dependent or small-cell derived PC cell lines and in 3 of 21 (14%) primary PCs from patients with androgen-dependent disease. Exposure of PC cells to the demethylating agent 5-aza-2'-deoxycytidine led to an increase in NEP transcripts in DU-145 and PC-3 cells. These data show that hypermethylation of the 5' CpG NEP island is associated with a loss of NEP expression in PC. Loss of NEP expression via hypermethylation of the NEP promoter may contribute to the development of neuropeptide-stimulated PCs.

Azacitidine↗
PubMed1999

Caveolin expression is decreased following androgen deprivation in human prostate cancer cell lines.

BACKGROUND: Increased expression of caveolin has been associated with prostate cancer progression. In a mouse reconstitution model of prostate cancer, expression of caveolin was inversely related to androgen sensitivity: androgen independent clones had high caveolin expression; low caveolin expression was associated with sensitivity to androgen withdrawal. In contrast, several independent observations support the hypothesis that caveolin functions as a tumor suppressor. METHODS: Caveolin expression was studied by Western blot analysis and/or immunohistochemistry in three androgen-sensitive human prostate cancer cell lines LNCaP, LAPC-4 and LAPC-9, and following acute and chronic androgen deprivation, and in benign prostate epithelial cells. Expression of caveolin, androgen receptor (AR) and prostate specific antigen (PSA) was also examined after reintroduction of androgen. RESULTS: LNCaP grown continuously under androgen-depleted conditions for 6 to 42 months produced several androgen-independent and tumorigenic clones: tumors formed in 13/15 castrate and 7/15 intact male athymic nu/nu mice, but no tumors formed in wildtype LNCaP-bearing animals. Caveolin expression was decreased in every androgen-deprived LNCaP clone and following 150 days of androgen deprivation in LAPC-4. Caveolin expression by LAPC-9 was very low. Following exposure to dihydrotestosterone in vitro, caveolin and PSA expression increased within three days in the androgen-deprived clones of LNCaP. Benign prostate epithelial cells have high caveolin expression. CONCLUSIONS: Unlike the mouse reconstitution model of prostate cancer, the pattern of caveolin expression in benign prostatic epithelium and androgen-sensitive human prostate cancer is consistent with tumor suppressive activity.

Animals↗
PubMed1999

Dynamics of prostate cancer cell invasion studied in vitro by NMR microscopy.

Understanding the dynamics and pathogenesis of invasion is vital for developing strategies to prevent cancer metastasis. Conventional invasion assays provide information for a single time point. NMR microscopic imaging as used in the current study to measure cell invasion in vitro provides a nondestructive method for scoring cell invasion thus offering a unique possibility to study this process dynamically. An additional advantage is that cells can be retrieved for metabolic and physiological characterization. Two prostate cancer cell lines, DU-145 and Mat-Ly-Lu, preselected for differences in invasive behavior, were studied. Cells were seeded in 12-mm culture plate inserts containing a 15-microm-thick porous membrane with 3.0 microm pore size that was coated with a 100 microm Matrigel layer. Cell invasion in the Matrigel layer was obtained from the profile of intracellular water measured with diffusion-weighted 1D imaging. Additional experiments were also performed with confocal microscopy to validate the NMR results. Significant differences were detected between the invasive behavior of DU-145 and Mat-Ly-Lu cells. The obtained results show that NMR microscopy can be used to dynamically study invasion by cancer cells. The noninvasive nature of NMR microscopy permits determination of cell migration dynamically for any given sample, which is especially important if cell availability is limited to the unique sample, such as for biopsy specimens. Magn Reson Med 42:277-282, 1999.

Animals↗
PubMed1999

New bone formation in an osteoblastic tumor model is increased by endothelin-1 overexpression and decreased by endothelin A receptor blockade.

OBJECTIVES: The osteoblastic response of bone to metastatic prostate cancer is both characteristic and enigmatic. The potent vasoconstrictor endothelin-1 (ET-1), produced by prostate cancer, has been identified as a potential factor in new bone formation. METHODS: Using a novel method to quantitate new bone formation induced by the WISH tumor, we examined the effects of ET-1 overexpression and endothelin receptor antagonists on the osteoblastic response. RESULTS: WISH, a human tumor cell line derived from amnion, produces ET-1 mRNA and protein and induces abundant new bone formation and splenomegaly in vivo. Stable transfection of WISH with an ET-1 overexpression cDNA construct produced clones that secreted 18-fold more bioactive ET-1 than vector-only controls. After 14 days of growth in the lower leg of nu/nu mice, ET-1 overexpressing tumors produced significantly more new bone than vector-only controls. Conversely, areas of new bone formation were significantly less in animals treated with a selective endothelin A (ET(A)) receptor antagonist A127722. CONCLUSIONS: The activity of ET-1 in this osteoblastic model provides a unique target for therapy.

Animals↗
PubMed1999

Laparoscopic retroperitoneal lymph node dissection for clinical stage I nonseminomatous germ cell testicular tumors.

OBJECTIVES: To assess retrospectively whether laparoscopic retroperitoneal lymph node dissection (RPLND) in patients with clinical Stage I nonseminomatous germ cell testicular tumor (NSGCT) provides useful pathologic staging information on which subsequent management can be based. Approximately 30% of patients with clinical Stage I NSGCT will have pathologic Stage II disease. METHODS: A retrospective review of 29 patients with clinical Stage I NSGCT who underwent transperitoneal laparoscopic RPLND by a single surgeon was performed. Selection criteria included the presence of embryonal carcinoma in the primary tumor or vascular invasion. A modified left (n = 18) or right (n = 11) template was used. RESULTS: Positive retroperitoneal nodes were detected in 12 (41%) of 29 patients. Ten of these patients received immediate adjuvant platinum-based chemotherapy, and 2 patients refused chemotherapy. The nodes were negative in 1 7 (59%) of 29 patients; all but 2 patients (one with recurrence in the chest, the other with biochemical recurrence) have undergone observation. No evidence of disease recurrence has been found in the retroperitoneum of any patient (follow-up range 1 to 65 months). Prospectively, the dissection was limited if grossly positive nodes were encountered; therefore, the total number of nodes removed was significantly different if the nodes were positive or negative (14 +/- 2 and 25 +/- 3, respectively; P <0.004). Two patients required an open conversion because of hemorrhage. Complications included lymphocele (n = 1) and flank compartment syndrome (n = 1). CONCLUSIONS: Laparoscopic RPLND is a feasible, minimally invasive surgical alternative to observation or open RPLND for Stage I NSGCT. Disease outcomes are favorable to date. Longer follow-up in a larger series is necessary to determine therapeutic efficacy.

Adult↗
PubMed1999

Prostate-specific antigen and other markers of therapeutic response.

Several new agents and combinations demonstrate significant activity in the treatment of patients with hormone refractory prostate cancer. Prostate-specific antigen (PSA) is being used increasingly as the key marker of a therapeutic response in trials of new agents. This article reviews data that support this marker as a surrogate endpoint, and it discusses the issues around the appropriateness of PSA as an intermediate marker with evolving noncytotoxic agents. Other biomarkers of prostate cancer progression are not uniformly elevated in men with advanced disease; to date, they are of limited clinical use. This article also discusses the rationale and results of novel and alternative biomarkers of prostate cancer progression.

Biomarkers, Tumor↗
PubMed1999

Stimulus generalization, context change, and forgetting.

Forgetting is often attributed to retrieval failure caused by background contextual cues changing over time. However, generalization between stimuli may increase over time and make them increasingly interchangeable. If this effect occurs with contextual cues, it might cancel any effect of a changing context. The authors review the evidence and suggest a resolution of this paradox. Although generalization gradients can change over time, the effect is not always strong. Increased responding to nontarget stimuli is not often shown, and few studies have demonstrated such changes with contextual cues in a way that rules out other interpretations. Even this example of forgetting may be caused by retrieval failure. The physical contexts manipulated in learning and memory experiments themselves occur within a superordinate temporal context and can thus be forgotten with no inherent challenge to a context-change account of forgetting.

Animals↗