Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Retinoids have been shown to have substantial anticancer activity in a number of preclinical and clinical situations. There are considerable epidemiologic, in vitro and in vivo data which indicate that retinoids may have a role in the prevention and therapy of human prostate cancer. Based on anecdotal evidence of response in one patient with hormone-refractory prostate cancer (HRPC), we conducted a phase II trial in HRPC during which we also examined changes in pharmacokinetics of all-trans-retinoic acid (ATRA) which occurred during therapy. Enrolled in the study were 17 patients with HRPC who received 50 mg/m2 ATRA three times daily orally on days 1-14, repeated every 22 days. The pharmacokinetics of ATRA were assessed with the first dose on day 1, again on day 14 and after a 7-day interruption in ATRA therapy on day 22. Patients were evaluable for response if they completed two 14-day courses of ATRA; among 13 such patients no responses were seen. Four patients were considered unevaluable for response owing to rapid disease progression in three and intercurrent illness in one. Apparent clearance of ATRA changed substantially during therapy: day 1 3779 +/- 4215 ml/min, day 14 7179 +/- 3197 ml/min, day 22 3213 +/- 2357 ml/min. Area under the curve was proportionately diminished on day 14 compared with day 1 and had returned to baseline by day 22. We conclude that ATRA is not active in HRPC. Failure of this agent in HRPC may be related to failure of drug delivery associated with enhanced mechanisms of ATRA clearance which occur within a few days of beginning ATRA treatment.
 ...
PMID:A phase II trial of all-trans-retinoic acid in hormone-refractory prostate cancer: a clinical trial with detailed pharmacokinetic analysis. 902 76

Recent studies have suggested that the active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3, can inhibit the growth and/or induce the differentiation of a variety of cell types and that these characteristics might be useful in the treatment of some cancers. Retinoids also promote the differentiation and inhibit the growth of some cells. That the vitamin D receptor acts as a heterodimer with the retinoid X receptor (RXR) suggests that there may be functional interactions between 1,25-dihydroxyvitamin D3 and retinoids. In this study, we show that the combination of 1,25-dihydroxyvitamin D3 and 9-cis retinoic acid synergistically inhibits the growth of LNCaP prostate cancer cells. That this effect is mediated by RXR rather than retinoic acid receptors was shown using RXR- and retinoic acid receptor-specific ligands. The vitamin D3 analog, EB1089, inhibited growth more effectively than 1,25-dihydroxyvitamin D3 and also acted synergistically with 9-cis-retinoic acid. These treatments caused cells to accumulate in the G1 phase of the cell cycle, suggesting that 1,25-dihydroxyvitamin D3 can regulate one or more factors critical for the G1/S transition.
 ...
PMID:1,25-dihydroxyvitamin D3 and 9-cis-retinoic acid act synergistically to inhibit the growth of LNCaP prostate cells and cause accumulation of cells in G1. 907 7

In the present paper, two strains of LNCaP cells derived from the same source (American Type Culture Collection), but studied either at a low passage number (LP) or at a high passage number (HP), were compared in their response to R1881 (a synthetic androgen), all-trans-retinoic acid (atRA), and 1alpha,25-dihydroxycholecalciferol (VD3). [3H]Thymidine incorporation and epidermal growth factor receptor (EGF-R) binding were measured as parameters related to the proliferative response of the cells. The secretion of prostate-specific antigen (PSA) and the mRNA expression of PSA, prostatic acid phosphatase (PAP), and diazepam-binding inhibitor (DBI) were used as parameters reflecting differentiated function. Marked differences were noted in the response of LP and HP cells to androgens. [3H]Thymidine incorporation displayed a bell-shaped dose-response curve in both strains. The amplitude of the response, however, was much higher in HP cells and growth inhibition at high levels of R1881 was only observed in LP cells. On the contrary, androgen induction of PSA secretion and PSA mRNA expression, as well as the expression of PAP was much more pronounced in LP cells, whereas DBI expression was not altered according to passage number. LP cells and HP cells also displayed striking differences in their response to atRA. An up to 6-fold stimulation of [3H]thymidine incorporation was observed in LP cells, whereas in HP cells the only significant effect was growth inhibition. VD3, on the contrary, inhibited [3H]thymidine incorporation to a comparable degree in LP and HP cells. Only marginal effects of atRA and VD3 were observed on PSA secretion. In both LP and HP cells EGF-R levels were increased by androgens and to a slight extent also by atRA and VD3. It is concluded that LP and HP LNCaP cells display markedly divergent responses not only to androgens but also to atRA. The proliferative rather than antiproliferative effects of atRA in some strains of LNCaP should caution against the uncontrolled use of these agents, or of drugs affecting their metabolism, in patients with prostate cancer.
 ...
PMID:LNCaP prostatic adenocarcinoma cells derived from low and high passage numbers display divergent responses not only to androgens but also to retinoids. 944 42

Understanding how the regulation of growth factor pathways alters during prostate cancer (PC) progression may enable researchers to develop targeted therapeutic strategies for advanced disease. PC progression involves the shifting of cells from androgen-dependent growth to an androgen-independent state, sometimes with the loss or mutation of the androgen receptors in PC cells. Both autocrine and paracrine pathways are up-regulated in androgen-independent tumors and may replace androgens as primary growth stimulatory factors in cancer progression. Our discussion focuses on growth factor families that maintain homeostasis between epithelial and stromal cells in the normal prostate and that undergo changes as PC progresses, often making stromal cells redundant. These growth factors include fibroblast growth factor, insulin-like growth factors, epidermal growth factor, transforming growth factor alpha, retinoic acid, vitamin D3, and the transforming growth factor beta families. We review their role in normal prostate development and in cancer progression, using evidence from clinical specimens and models of PC cell growth.
 ...
PMID:Growth factor involvement in progression of prostate cancer. 955 81

Troglitazone, a thiazolidinedione derivative, is a widely used antidiabetic drug that binds and activates peroxisome proliferator-activated receptor gamma (PPARgamma) and enhances insulin sensitivity. It induces differentiation of adipocytes, which highly express PPARgamma. We report that human prostate cancer cells expressed PPARgamma at prominent levels and normal prostate tissues had very low expression. Dose-response clonogenic assays of the PC-3 prostate cancer cell line with troglitazone showed an antiproliferative effect (ED50, 3 x 10(-7) M) and other PPARgamma ligands (BRL49653: ED50, 8 x 10(-8) M; 15-deoxy-delta12,14-prostaglandin J2: ED50, 2 x 10(-6) M; ciglitizone: ED50, not reached; indomethacin: ED50, not reached) showed similar effects. Combinations of troglitazone and a ligand specific for either retinoid X receptor or retinoic acid receptor did not show a synergistic effect. Pulse-exposure to troglitazone (10(-5) M) for different durations showed that 4 days of pulse-exposure to the agent irreversibly inhibited 50% clonal growth of PC-3 cells. Interestingly, PC-3 cells cultured with troglitazone (10(-5) M) showed dramatic morphological changes both by light and electron microscopy, suggesting that the cells became less malignant. Nevertheless, troglitazone did not affect either the cell cycle or several markers of differentiation. LNCaP cells constitutively produced prostate-specific antigen, and levels were markedly enhanced by all-trans-retinoic acid. Troglitazone (10(-5) M, 4 days) decreased by 50% the levels of prostate-specific antigen produced by these cells. In vivo treatment of PC-3 tumors growing in male BNX triple immunodeficient mice with oral troglitazone (500 mg/kg/day) produced significant inhibition of tumor growth (P = 0.01). The only objective side effect of troglitazone in mice was the elevation of serum transaminases. Short-term culture of four surgically obtained human prostate cancer tumors with troglitazone (10(-5) M, 4 days) produced marked and selective necrosis of the cancer cells (about 60%) but not the adjacent normal prostate cells. Taken together, these results suggest that troglitazone may be a useful therapeutic agent for the treatment of prostate cancer, especially in the setting of low disease burden.
 ...
PMID:Ligand for peroxisome proliferator-activated receptor gamma (troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo. 969 65

Liarozole (Liazal) is the first retinoic acid (RA) metabolism blocking agent (RAMBA) in clinical practice. RAMBA therapy promotes differentiation and inhibits proliferation by increasing endogenous RA in tumours. Liarozole was investigated in two open-label pilot studies of 100 patients with progressive prostate cancer in relapse despite previous androgen ablation. Liarozole (150-300 mg twice daily, for > or = 1 month) produced > or = 50% reduction in prostate specific antigen (PSA) serum levels in 15 of 30 evaluable patients in study 1 (50%) and 10 of 55 patients in study 2 (18%). PSA responders had more marked reductions in prostatic acid phosphatase, alkaline phosphatase and symptom scores for bone pain and urological symptoms, and improved general well being. Plasma levels of adrenal androgens did not alter during chronic treatment with liarozole nor at adrenocorticotrophic hormone (ACTH) stimulation test. Liarozole did not alter plasma levels of adrenal androgens or cortisol. Cortisol response to ACTH stimulation was slightly blunted. Liarozole was generally well tolerated. Dermatological adverse events were probably related to increased intracellular RA. Liarozole appears to be a promising treatment option in prostate cancer.
 ...
PMID:Early clinical experience with liarozole (Liazal) in patients with progressive prostate cancer. 971 90

Endothelin-1 (ET-1) is not only a potent vasoconstrictor but also serves as an important growth stimulator in various cancers, including breast, cervical, pancreatic, and prostate cancer. This suggests that blockage of ET-1 production may suppress tumor growth and possibly metastasis. We observed that certain synthetic retinoids, and all-trans-retinoic acid can repress LNCaP prostate cancer cell growth in vitro. In addition, these retinoid compounds counteracted exogenous ET-1-induced growth stimulation. Retinoid-dependent growth retardation of LNCaP cells coincided with suppression of ET-1 gene expression to a level undetectable by reverse transcription-PCR. Contrarily, the androgen-insensitive DU145 cells were refractory to retinoid treatment. To investigate the underlying mechanisms of the cell-specific response to retinoids, we transfected ET-1 promoter constructs containing wild-type or mutated AP-1 or GATA-2 site into prostate cancer cells. Distinct regulations of ET-1 promoter activity were found; in LNCaP cells, both binding sites are essential for optimal promoter activation, whereas in DU145 cells, additional promoter sequences and/or transcriptional factors seem to be involved. Furthermore, several anti-AP-1 selective retinoids failed to repress ET-1 promoter activity and to exhibit a cell growth-inhibitory effect on LNCaP cells, suggesting that different retinoid structural configurations are required for the inhibition of an AP-1 complex versus an AP-1/GATA-2 complex.
 ...
PMID:ET-1 expression and growth inhibition of prostate cancer cells: a retinoid target with novel specificity. 980 84

The objective of this study was to test the hypothesis that 13-cis-retinoic acid (CRA) and alpha-interferon (IFN-alpha) have antitumor activity in patients with early recurrence of prostate cancer measured by rising prostate-specific antigen (PSA) after local therapy, and that this activity is associated with the increase of plasma transforming growth factor beta1 (TGF-beta1). Thirty patients with a PSA > 7 ng/ml that increased >0.4 ng/ml/month after initial radiation therapy or a PSA > 2.0 ng/ml after prostatectomy were treated with 1 mg/kg/day of CRA and 3 million units of IFN-alpha administered three times per week. Patients were followed clinically with serum measurements of PSA and assessment of toxicity. Biological activity of CRA and IFN-alpha was assessed by the measurement of plasma TGF-beta1. Twenty-six percent of patients had a partial (50% decrease maintained for 1 month) or minimal (<50% decrease maintained for 1 month) biochemical response of PSA, with a median decrease of 23% (11-55%) at 3 months. Plasma TGF-beta1 levels increased with CRA and IFN-alpha therapy and correlated with a decrease in PSA; patients with a decrease in PSA had a 151% increase in TGF-beta1 compared to 27% in patients without a decrease in PSA (P = 0.04). CRA and IFN-alpha can produce transient reduction or stabilization of PSA. The measurement of plasma TGF-beta1 at 1 month of therapy correlates with changes in PSA and may represent a useful marker for the biological effect of these agents; further analysis in larger numbers of patients and methods to optimize these effects should be explored.
 ...
PMID:Effect of 13-cis-retinoic acid and alpha-interferon on transforming growth factor beta1 in patients with rising prostate-specific antigen. 981 90

Effects of all-trans retinoic acid (RA) on the net enzymatic activity of secreted, extracellular urokinase-type plasminogen activator (u-PA) in DU-145 human prostatic carcinoma cells were examined to assess the potential use of retinoids in human prostate cancer prevention and treatment. u-PA is associated with tumor progression involving invasion and metastasis. Based on a chromogenic substrate assay, results show that DU-145 cells secrete five times more u-PA than normal human prostatic epithelium. DU-145 cells were treated with 0.1 to 10 micrometer RA for 48 h. This short treatment of cells with RA did not inhibit growth. After a 48-h treatment of cultures with RA, serum-free conditioned medium was analyzed for u-PA activity by SDS-PAGE zymography. Two major bands of u-PA with Mr of approximately 54,000 (high molecular weight u-PA) and approximately 33,000 (low molecular weight u-PA) were detected. Plasminogen-dependent catalytic activity of these bands could be specifically inhibited with antibody to u-PA, confirming that these bands represent u-PA. A 48-h treatment with 1.0 micrometer RA reduced u-PA activity in conditioned medium to 51.6% of control. A 50% reduction in free u-PA antigen level, as compared to control, was further demonstrated at 1.0 micrometer RA by Western blot analysis and densitometry. These results show that RA can decrease the net extracellular urokinase activity produced by prostatic carcinoma cells. It is proposed that these effects of RA may have important implications not only in the chemoprevention of prostate cancer, by inhibition of promotion of prostatic intraepithelial neoplasia to invasive carcinoma, but also in tumor progression during invasion and metastasis, by decreasing extracellular matrix degradation, as shown in our accompanying article (M. M. Webber and A. Waghray, Clin. Cancer Res., 1: 755-761, 1995).
 ...
PMID:Retinoic acid modulates extracellular urokinase-type plasminogen activator activity in DU-145 human prostatic carcinoma cells. 981 41

Both normal and malignant prostatic epithelial cells in culture secrete urokinase-type plasminogen activator (u-PA) into the culture medium. u-PA has been shown to have a direct association with invasive and metastatic potential of many types of cancers. We propose that prostate cancer has the intrinsic ability to invade and metastasize because of its inherent ability to secrete the serine protease u-PA. We further propose that in prostate cancer, u-PA is the key enzyme which occupies a place at the apex of the proteolytic cascade and initiates the degradative process. Subsequently, collagenases are recruited after activation of procolla-genases by another serine protease plasmin formed by the activation of plasminogen by u-PA. Extracellular proteolysis involving plasmin can cause massive degradation of the extracellular matrix. We show that u-PA alone can use fibronectin as a substrate and degrade it, but u-PA alone did not degrade laminin. Serum-free conditioned medium from DU-145 human prostatic carcinoma cells has the ability to degrade both fibronectin and laminin. However, treatment of cultures with 1 microM all-trans retinoic acid (RA) for 48 h reduced the ability of serum-free conditioned medium to cause u-PA-mediated degradation of fibronectin and laminin. Thus, RA had a protective effect on these extracellular matrix glycoproteins. Treatment of cells with RA also decreased their ability to invade Matrigel in the in vitro invasion assay in a dose-dependent manner. RA at the 0.5, 1, and 10 microM level reduced invasion to 65.7%, 46.7%, and 34.3% of control, respectively. RA reduced extracellular proteolysis and thus inhibited extracellular matrix degradation and invasion. These results may also explain one mechanism by which retinoids inhibit invasion and metastasis in vitro and in vivo. These studies have important translational value in the chemoprevention of progression of prostatic intraepithelial neoplasia to invasive carcinoma.
 ...
PMID:Urokinase-mediated extracellular matrix degradation by human prostatic carcinoma cells and its inhibition by retinoic acid. 981 42


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>