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

Genitourinary cancers--bladders, testis and prostate--account for almost 50,000 deaths per year. Epidemiologic data suggest that individuals with low serum retinoid levels or low dietary intake of retinoid-containing foodstuffs have an increased risk of bladder and prostate cancer. Preclinical investigations show that a variety of retinoids suppress the proliferation of prostate and bladder cancer cells and induce differentiation in teratocarcinoma cells. Retinoids prevent the emergence of murine bladder and prostate cancers in carcinogen-treated animals. Clinical data are disappointing or inconclusive. A single well-conducted phase 2 trial of 13-cis retinoic acid in patients with germ cell tumors was negative. Several historically controlled as well as prospectively randomized, placebo-controlled trials of retinoids in superficial bladder cancer have failed to provide evidence of the efficacy of retinoids. Two studies of all-trans-retinoic acid in advanced prostate cancer have been negative. Despite compelling preclinical rationale, retinoids have failed to yield positive results in the clinical management of prostate, bladder or testis cancers. Further work is needed to define subsets of patients in whom retinoids might be active, and whether new retinoids or new approaches to retinoid delivery will improve the clinical usefulness of retinoids in these tumors.
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PMID:Retinoids in bladder, testis and prostate cancer: epidemiologic, pre-clinical and clinical observations. 780 25

The addition of lipid hydroperoxides greatly accelerates the rate of oxidative catabolism of all-trans-retinoic acid (RA) in human cell microsomes; hydroperoxy metabolites of the arachidonate cascade are particularly active in the microsomal system. We have measured the plasma content of lipid peroxides in cancer patients during the course of therapy with RA, seeking to assess whether a correlation exists between the rate of oxidative catabolism of exogenously administered RA and whole body lipid peroxide levels. The assay used for plasma lipid peroxides is the capacity to react with thiobarbituric acid under specified conditions; the result is expressed as TBARS (thiobarbituric acid reactive substances). RA administration produced its own accelerated clearance RA within 72 h. Patients were considered to have "normal" or "rapid" baseline catabolism of RA if their Day 1 area under RA concentration over time curve was greater or less than 300 ng.h/ml, respectively. The mean plasma TBARS levels were: 12 normal volunteers = 0.14 microM; 19 "normal" RA catabolizers = 0.25 microM; and 14 "rapid" catabolizers = 0.82 microM. P = 0.008 (rapid catabolizers versus normal volunteers) and 0.05 (rapid catabolizers versus normal catabolizers). Repeat TBARS determinations were made during the course of therapy in 17 patients, all of whom converted to "rapid" RA catabolism on therapy. An increase in plasma TBARS levels > or = 20% of baseline was observed in 5 of 5 prostate cancer patients and 8 of 12 lung cancer patients treated with continuous RA therapy for 2 and 4 weeks, respectively. These observations support the hypothesis that high levels of lipid peroxides and rapid oxidative catabolism of RA are positively correlated.
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PMID:Elevated plasma lipid peroxide content correlates with rapid plasma clearance of all-trans-retinoic acid in patients with advanced cancer. 817 17

There is increasing evidence that growth and differentiation of prostatic carcinoma cells may be modulated not only by androgens and growth factors but also by vitamin D, retinoids, and phenylacetate (PA). The latter agonists may have a role in the prevention and therapy of prostate cancer but their exact therapeutic potential remains unclear. Since both retinoids and vitamin D act via nuclear receptors, the same way androgens do, we studied the interactions of these compounds with androgen-induced proliferation and differentiation using LNCaP cells as a model of androgen-responsive tumor cells. PA was included because of its suspected different mode of action [H3]-thymidine incorporation was used as a measure of proliferative activity, secretion of prostate-specific antigen (PSA) as a measure of differentiated function. The present data show that 1alpha,25-dihydroxycholecalciferol (VD3), all-trans retinoic acid (atRA), 9-cis retinoic acid (9cRA), and PA stimulated LNCaP cell-differentiated function in the presence or absence of androgens. The effects on cell growth were more complicated. In the absence of androgens growth stimulatory effects were observed for the retinoids and under some conditions for VD3. These effects were limited, however, and tended to be more pronounced at low cell densities. In the presence of androgens nearly exclusively growth inhibitory effects were observed. On a molar basis VD3 was the most effective antiproliferative agonist (ED50 = 10(-9) M). It completely neutralized the stimulatory effects of androgens. Growth inhibition was not due to a decrease in the concentration of androgen receptor: whereas atRA, 9cRA, and PA did not alter androgen receptor levels, VD3 provoked a twofold increase. Neither in the presence nor in the absence of androgens did we observe any cooperativity in the growth stimulatory or inhibitory effects of VD3, atRA, or 9cRA. To test whether treatment with any of the studied agonists resulted in a phenotypic reversion and sustained growth arrest, LNCaP cells were pretreated with VD3, atRA, 9cRA, or PA for 6-12 days and reseeded at equal densities as untreated cells. In all cases tested [3H]-thymidine incorporation was restored within 6 days suggesting that none of these compounds caused irreversible growth inhibition.
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PMID:Control of LNCaP proliferation and differentiation: actions and interactions of androgens, 1alpha,25-dihydroxycholecalciferol, all-trans retinoic acid, 9-cis retinoic acid, and phenylacetate. 862 21

The prostatic-specific antigen (PSA) is the tumor marker most widely relied upon for the monitoring of patients with prostate cancer. Recently, declines in the serum concentrations of PSA have been advocated as a surrogate marker of tumor response in clinical trials of investigational antitumor agents. We examined the hypothesis that this postulate may not apply to the evaluation of drugs such as phenylacetate, a differentiating agent endowed with mechanisms of action different from those of classic cytotoxic chemotherapy. Using human prostatic carcinoma LNCaP cells as a model, we show that phenylacetate induces PSA production despite inhibition of tumor cell proliferation. Incubation of LNCaP cultures with cytostatic doses of phenylacetate (3-10 mM) resulted in a three- to fourfold increase in PSA secretion per cell. This appears to result from upregulation of PSA gene expression, as indicated by elevated PSA mRNA steady-state levels in treated cells. The increase in PSA production per cell was confirmed in rats bearing subcutaneous LNCaP tumor implants that were treated systemically with phenylacetate. Further comparative studies indicate that upregulation of PSA is common to various differentiation inducers, including all-trans-retinoic acid, 1,25-dihydroxyvitamin D3, and butyrate but is not induced by other antitumor agents of clinical interest such as suramin. We conclude that declines in PSA may be treatment specific and that the exclusive use of this criterion as a marker of disease response may mislead the proper evaluation of differentiating agents in prostate cancer patients.
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PMID:The differentiating agent phenylacetate increases prostate-specific antigen production by prostate cancer cells. 882 86

An evaluation of the Health Professionals Follow-Up Study has detected a lower prostate cancer risk associated with the greater consumption of tomatoes and related food products. Tomatoes are the primary dietary source of lycopene, a non-provitamin A carotenoid with potent antioxidant activity. Our goal was to define the concentrations of lycopene, other carotenoids, and retinol in paired benign and malignant prostate tissue from 25 men, ages 53 to 74, undergoing prostatectomy for localized prostate cancer. The concentrations of specific carotenoids in the benign and malignant prostate tissue from the same subject are highly correlated. Lycopene and all-trans beta-carotene are the predominant carotenoids observed, with means +/- SE of 0.80 +/- 0.08 nmol/g and 0.54 +/- 0.09, respectively. Lycopene concentrations range from 0 to 2.58 nmol/g, and all-trans beta-carotene concentrations range from 0.09 to 1.70 nmol/g. The 9-cis beta-carotene isomer, alpha-carotene, lutein, alpha-cryptoxanthin, zeaxanthin, and beta-cryptoxanthin are consistently detectable in prostate tissue. No significant correlations between the concentration of lycopene and the concentrations of any other carotenoid are observed. In contrast, strong correlations between prostate beta-carotene and alpha-carotene are noted (correlation coefficient, 0.88; P < 0.0001), as are correlations between several other carotenoid pairs, which reflects their similar dietary origins. Mean vitamin A concentration in the prostate is 1.52 nmol/g, with a range of 0.71 to 3.30 nmol/g. We further evaluated tomato-based food products, serum, and prostate tissue for the presence of geometric lycopene isomers using high-performance liquid chromatography with a polymeric C30 reversed phase column. All-trans lycopene accounts for 79 to 91% and cis lycopene isomers for 9 to 21% of total lycopene in tomatoes, tomato paste, and tomato soup. Lycopene concentrations in the serum of men range between 0.60 and 1.9 nmol/ml, with 27 to 42% all-trans lycopene and 58 to 73% cis-isomers distributed among 12 to 13 peaks, depending upon their chromatographic resolution. In striking contrast with foods, all-trans lycopene accounts for only 12 to 21% and cis isomers for 79 to 88% of total lycopene in benign or malignant prostate tissues. cis Isomers of lycopene within the prostate are distributed among 14 to 18 peaks. We conclude that a diverse array of carotenoids are found in the human prostate with significant intra-individual variation. The presence of lycopene in the prostate at concentrations that are biologically active in laboratory studies supports the hypothesis that lycopene may have direct effects within the prostate and contribute to the reduced prostate cancer risk associated with the reduced prostate cancer risk associated with the consumption of tomato-based foods. The future identification and characterization of geometric lycopene isomers may lead to the development of novel agents for chemoprevention studies.
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PMID:cis-trans lycopene isomers, carotenoids, and retinol in the human prostate. 889 94

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.
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PMID:A phase II trial of all-trans-retinoic acid in hormone-refractory prostate cancer: a clinical trial with detailed pharmacokinetic analysis. 902 76

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.
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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

Hormonally insensitive prostate cancer is a relatively slow-growing, but usually fatal, disease with no long-term treatment options. Transformation of normal prostate cells to a malignant phenotype often involves corruption of the apoptotic machineries. Bcl-2 protein is one of the key inhibitors of apoptosis and is often unregulated in advanced prostate cancer. The prostate cancer cell line DU-145 was used as a model of a hormonally insensitive, advanced prostate cancer. Cell growth in liquid culture was significantly inhibited by antisense Bcl-2 oligonucleotides compared with control sense oligonucleotides; inhibition by these oligonucleotides was significantly enhanced on combination with the synthetic retinoid N-(2-hydroxyphenyl)all-trans-retinamide (2-HPR). Interestingly, growth inhibition occurred in the absence of apoptosis as measured using two assay techniques. We hypothesize that in these recalcitrant cells the apoptotic pathway is compromised at several levels, and Bcl-2 may play another role in promoting cell growth. The use of Bcl-2 antisense oligonucleotides plus 2-HPR may provide a novel approach to therapy of hormone-resistant prostate cancer.
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PMID:Growth inhibition of DU-145 prostate cancer cells by a Bcl-2 antisense oligonucleotide is enhanced by N-(2-hydroxyphenyl)all-trans retinamide. 951 52

The influence of chemical carcinogen, hormonal stimulation, and chronic dietary administration of the synthetic retinoid, N-(4-hydroxyphenyl)-all-trans-retinamide (4-HPR), on the induction of prostate cancer in male Wistar-Unilever rats was determined. Three different tumor induction regimens were used: (a) a single i.v. dose of 50 mg of N-methyl-N-nitrosourea (MNU) per kg body weight, followed by chronic androgen stimulation via s.c. implantation of two silastic capsules containing 40 mg testosterone each; (b) a single i.v. dose of 50 mg of MNU per kg body weight (no testosterone treatment); and (c) chronic androgen stimulation with implanted testosterone capsules (no MNU treatment). In a fourth series of animals, the incidence of spontaneous prostate tumors was determined in groups of rats receiving neither carcinogen nor hormone stimulation. Within each series, parallel groups of animals were fed a control (vehicle-supplemented) diet or control diet supplemented with 4-HPR beginning 1 day after carcinogen administration; retinoid administration was continuous until termination of the study at 450 days. The incidence of accessory sex gland cancer in rats treated sequentially with MNU + testosterone was >60%, in comparison with cancer incidences of <20% in rats receiving MNU only and <5% in rats treated with testosterone only. No spontaneous accessory sex gland tumors were observed in rats receiving no carcinogen and no testosterone. Tumor induction in the accessory sex glands by MNU + testosterone was relatively specific for the prostate: the incidence of carcinoma of the dorsolateral/anterior prostate was more than 5-fold greater than the incidence of cancer present only in the seminal vesicle. 4-HPR conferred no protection against cancer induction in the prostate by any regimen of MNU and/or testosterone. These results demonstrate the importance of both carcinogen exposure and hormone stimulation on the induction of neoplasia in the prostate of Wistar-Unilever rats.
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PMID:Influence of N-methyl-N-nitrosourea, testosterone, and N-(4-hydroxyphenyl)-all-trans-retinamide on prostate cancer induction in Wistar-Unilever rats. 969 56

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.
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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


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