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)

The results of cytotoxic chemotherapy for advanced, hormone-escaped prostate cancer have been disappointing. Evaluation of the effect of new drugs or new combinations with already known ones is required. The antimetabolite 5-fluorouracil (5-FU) has been shown to be active in prostate cancer, acting via inhibition of thymidylate synthase, an essential enzyme in DNA de novo synthesis. Experiments with cell lines of different tumors have shown that 5-FU activity can be modulated by addition of the coenzyme tetrahydrofolic acid (folinic acid). We investigated the effect of folinic acid and its stereoisomers on 5-FU action in different cell lines of prostate cancer. It was found that addition of non-toxic folinic acid led to a two- to fourfold better antiproliferative effect of 5-FU. The unnatural 6R isomer, which is a compound of chemically synthesized folinic acid, inhibited the modulatory effect of the natural 6S isomer. Our results indicated that a combination of folinic acid and 5-FU may result in a better response of patients with hormone-resistant prostate cancer than of patients treated with 5-FU alone.
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PMID:Biomodulation of 5-Fu cytotoxicity by folinic acid and its stereoisomers: in vitro experiments with different cell lines of prostatic cancer. 748 42

Androgen-independent Dunning R-3327 AT-3 rat prostatic cancer cells can be induced to undergo programmed cell death in either a proliferation-dependent or independent manner depending upon the therapeutic agent used. In the present study, 5-fluorodeoxyuridine (5-FrdU) was used to induce proliferation-dependent death of the AT-3 cells via its ability to inhibit thymidylate synthetase. Ionomycin and thapsigargin were used to induce proliferation-independent death of these cells via their ability to sustain an elevation in intracellular free Ca2+. Based upon the temporal sequence of DNA fragmentation, morphologic changes, and loss of cell viability, each of the three test agents, at the doses used, induces the programmed death of AT-3 cells with essentially identical kinetics. Based upon these similarities, comparisons of the pattern of gene expression during the proliferation-dependent (i.e., 5-FrdU-induced) vs. proliferation-independent (i.e., ionomycin and thapsigargin-induced) programmed death of AT-3 cells allow identification of genes whose enhanced expression is involved in the initiation vs. completion of programmed cell death. Based upon this approach, enhanced H-ras and TRPM-2 expression is associated with initiation of proliferation-dependent programmed death of AT-3 cells while enhanced c-myc, calmodulin, and alpha-prothymosin expression is associated with initiation of proliferation-independent programmed death of these cells. In contrast, enhanced expression of glucose-regulated 78 kilodalton and tissue transglutaminase genes are associated with the completion of programmed cell death, since their expression is enhanced in both proliferation-dependent and independent programmed cell death of AT-3 cells.
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PMID:Proliferation-dependent vs. independent programmed cell death of prostatic cancer cells involves distinct gene regulation. 799 34

At a nontoxic growth inhibitory concentration benzyloxyacyclouridine (BAU), a potent and specific inhibitor of uridine phosphorylase (UrdPase), enhanced 5-fluorouracil (5-FU) cytotoxic activity against human prostate cancer PC-3 and DU-145 cell lines. The BAU/5-FU combination exhibited greater antitumor activity in vivo using PC-3 human xenografts compared to 5-FU alone, with no associated increase in animal host toxicity. The mechanism(s) responsible for the enhanced in vitro and in vivo activity of this combination may involve enhanced formation of the 5-FU nucleotide metabolites FdUMP, FdUTP, and FUTP resulting in enhanced inhibition of thymidylate synthase (TS) and increased incorporation of fluoropyrimidine metabolites into tumoral RNA and DNA.
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PMID:Benzylacyclouridine enhances 5-fluorouracil cytotoxicity against human prostate cancer cell lines. 949 66

Fluorodeoxyuridine (5-FdUrd) is an antineoplastic agent with clinical activity against different types of solid tumours. To enhance the effectiveness of this drug, we have synthesised new heterodinucleoside phosphate dimers of 5-FdUrd. These dimers were compared to 5-FdUrd for their cytotoxic effect and the cell cycle dependence of cytotoxicity, as well as for their capacity to induce apoptosis and inhibit thymidylate synthetase (TS) in androgen-independent human PC-3 prostate tumour cells. Incubation of the cells with the dimers N(4)-palmitoyl-2'-deoxycytidylyl-(3'-->5')-5-fluoro-2'-deoxyuri din e (dCpam-5-FdUrd) and 2'-deoxy-5-flourouridylyl-(3'-->5')-2'-deoxy-5-fluoro-N(4)-octa decylc ytidine (5-FdUrd-5-FdC18) resulted in a marked cytotoxicity with IC(50) values of 4 microM, similar to 5-FdUrd. In contrast to 5-FdUrd, 100% toxicity was achieved with concentrations of 100-200 microM 5-FdUrd-5-FdC18. Flow cytometric analysis revealed an increase in the cell population in S-phase after treatment with 5-FdUrd, 5-FdUrd-5-FdC18, and dCpam-5-FdUrd from 36 to 63%, 50%, and 77%, respectively. dCpam-5-FdUrd was more potent than 5-FdUrd in arresting the cell cycle. Significant S-phase arrest was indicated by a decreased proportion of cells in G1- and G2/M-phases. Cell cycle arrest and inhibition of cell proliferation were followed by apoptosis, as shown by a 6- to 8-fold increased binding of Apo2.7 antibody, a 9- to 11-fold increase in caspase-3 activity, DNA fragmentation, and by cell morphology showing the appearance of apoptotic bodies. Importantly, 5-FdUrd-5-FdC18 increased the number of apoptotic cells to 160% compared to 5-FdUrd under the same conditions. As with 5-FdUrd, the two dimers also inhibited TS in a time- and concentration-dependent manner, although requiring 100-fold higher concentrations. In conclusion, dCpam-5-FdUrd and 5-FdUrd-5-FdC18 exert stronger cytotoxicity and induce more S-phase arrest and apoptosis than does 5-FdUrd in PC-3 cells, suggesting their potential role in the treatment of human prostate cancer.
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PMID:Induction of cell cycle-dependent cytotoxicity and apoptosis by new heterodinucleoside phosphate dimers of 5-fluorodeoxyuridine in PC-3 human prostate cancer cells. 1110 5

Tumor cells are more sensitive to methionine restriction than normal tissues, a phenomenon known as methionine auxotrophy. Previous studies showed that 5-fluorouracil and methionine restriction act synergistically against a variety of tumors. The purpose of the current studies was to determine the molecular mechanism(s) underlying this synergy. 5-Fluorouracil is known to inhibit thymidylate synthase (TS), a key enzyme that transfers a methyl group from 5,10-methylene-tetrahydrofolate to dUMP during nucleotide biosynthesis. We found that methionine restriction reduced 5,10-methylene-tetrahydrofolate levels by 75% and selectively inhibited TS activity in PC-3 human prostate cancer cells within 24hr, whereas it did not in normal prostate epithelial cells. The observed fall in TS activity was accompanied by a commensurate reduction in TS protein levels as determined by western blot analysis. In contrast, 5-fluorouracil inhibited TS activity by >90% but increased TS protein levels. This increase was abrogated by methionine restriction. Surprisingly, methionine restriction increased 3H-leucine incorporation in PC-3 cells over the first 24hr, suggesting that reduction of TS levels was not simply due to global protein synthesis inhibition. Methionine restriction also significantly reduced the ratio of dUMP to dTTP in PC-3 cells, creating an imbalanced nucleotide pool. These results suggest that synergy between methionine restriction and 5-fluorouracil is attributable to multiple factors, including depletion of reduced folates, selective inhibition of TS, and creation of an imbalanced nucleotide pool. Dietary and/or enzymatic methionine restriction combined with 5-fluoruracil has great promise as a novel treatment for advanced cancer.
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PMID:Methionine restriction selectively targets thymidylate synthase in prostate cancer cells. 1294 60

SR31747A is a sigma ligand that exhibits a potent antitumoral activity on various human tumor cell lines both in vitro and in vivo. To understand its mode of action, we used DNA microarray technology combined with a new bioinformatic approach to identify genes that are modulated by SR31747A in different human breast or prostate cancer cell lines. The SR31747A transcriptional signature was also compared with that of seven different representative anticancer drugs commonly used in the clinic. To this aim, we performed a two-dimensional hierarchical clustering analysis of drugs and genes which showed that 1) standard molecules with similar mechanism of action clustered together and 2) SR31747A does not belong to any previously characterized class of standard anticancer drugs. Moreover, we showed that 3) SR31747A mainly exerted its antiproliferative effect by inhibiting the expression of genes playing a key role in DNA replication and cell cycle progression. Finally, contrasting with other drugs, we obtained evidence that 4) SR31747A strongly inhibited the expression of three key enzymes of the nucleotide synthesis pathway (i.e., dihydrofolate reductase, thymidylate synthase, and thymidine kinase) with the latter shown both at the mRNA and protein levels. These results, obtained through a novel molecular approach to characterize and compare anticancer agents, showed that SR31747A exhibits an original mechanism of action, very likely through unexpected targets whose modulations may account for its antitumoral effect.
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PMID:Transcriptomic classification of antitumor agents: application to the analysis of the antitumoral effect of SR31747A. 1468 86

The alpha2-macroglobulin signalling receptor is upregulated in highly metastatic 1-LN prostate cancer cells. Stimulation of 1-LN cells with activated alpha2-macroglobulin (alpha2M*) caused a two- to threefold increase in [3H]thymidine uptake and cell number. These events require the Ras-dependent MAPK and PI 3-kinase/Akt signalling cascades. Incubation of 1-LN cells with alpha2M* induced Grb2, shc, sos and Raf-1 expression, as well as phosphorylation of MEK 1/2, ERK 1/2, p38 MAPK and JNK. This treatment also increased PI 3-kinase activation, PDK1 expression, Akt phosphorylation and p70s6k phosphorylation. Levels of the early gene products c-fos protein and thymidylate synthase were comparably increased. Exposure of 1-LN cells to alpha2M* significantly raised the levels of phosphorylated CREB by about 15-20 min and phosphorylated p53 by about 60-90 min of incubation. We conclude that the growth regulatory effects of ligating the alpha2M* signalling receptor on 1-LN cells are exerted via the onset and crosstalk between the Ras-dependent MAPK and PI 3-kinase/Akt signalling cascades.
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PMID:Potentiation of signal transduction mitogenesis and cellular proliferation upon binding of receptor-recognized forms of alpha2-macroglobulin to 1-LN prostate cancer cells. 1470 37

Single-agent docetaxel (Taxotere) treatment has recently demonstrated promising clinical activity in patients with advanced hormone-refractory prostate cancer. Taxanes were recently found to upregulate the tumoral activity of thymidine phosphorylase (TP), a key cellular enzyme [transformation of 5'-deoxy-5-fluorouridine (5'-DFUR) into 5-fluorouracil] in the activation cascade of capecitabine (Xeloda). We tested (cytotoxic effects and molecular mechanisms) the Taxotere-5'-DFUR combination on hormone-refractory prostate cancer cell lines (DU145 and PC3). Cells were exposed to Taxotere and/or 5'-DFUR in three different sequences: Taxotere was given alone for 48 h, then 5'-DFUR was added for 48 h; Taxotere and 5'-DFUR together during 96 h or 5'-DFUR was given alone for 48 h then Taxotere was added for 48 h. The drug sequence Taxotere applied first followed by 5'-DFUR led to synergistic cytotoxic effects on both cell lines; the other sequences resulted in simple additivity. Taxotere did not modify TP activity while it decreased thymidylate synthase activity. There was an increase in CD95 cellular membrane levels following exposure to Taxotere-5'-DFUR, which is in agreement with the supra-additive cytotoxic combination. This observation may serve as a preclinical rationale for a next step testing the Taxotere-capecitabine combination at the clinical level in prostate cancer patients.
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PMID:Taxotere-5'-deoxy-5-fluorouridine combination on hormone-refractory human prostate cancer cells. 1571 Nov 83

The enzymes thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), and orotate phosphoribosyl transferase (OPRT) are involved in the metabolism of the anticancer drug 5-fluorouracil. No reports have examined the expression of these enzymes in prostate cancer (CaP). A total of 25 previously untreated, hormone-sensitive CaP tissue samples and 11 benign prostatic hyperplasia (BPH) specimens were examined. Tissue of CaP and BPH tissue samples were obtained from formalin-fixed, paraffin-embedded sections by laser-captured microdissection, and then RNA was extracted. mRNA expression of TS, DPD, TP, and OPRT was analyzed by quantitative reverse transcriptase-polymerase chain reaction. TS and OPRT expression levels were significantly higher in CaP samples than in BPH. DPD expression level in poorly differentiated CaP was significantly lower than that in CaP with more favorable--well or moderately differentiated--histopathology.
Prostate Cancer Prostatic Dis 2005
PMID:Expression of thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, and orotate phosphoribosyl transferase in prostate cancer. 1599 19

The current reference treatment of hormone-refractory prostate cancer consists mainly of chemotherapy with docetaxel. To improve the management of advanced prostate cancer, one should examine the benefits of adding other agents to docetaxel. We examined the growth inhibitory effects of a triple combination, including the anti-epidermal growth factor receptor drug erlotinib, docetaxel and 5-fluoro-5'-deoxyuridine (the main intermediary metabolite of capecitabine), on the human prostate cancer cell lines PC3 and DU145, which are both devoid of androgen receptors. Marked synergistic cytotoxic effects were observed with the application of the double combination of erlotinib-5-fluoro-5'-deoxyuridine for both cell lines and to a lesser magnitude with the triple combination. For PC3 cells, all conditions resulted in synergistic interactions. The combination between erlotinib and docetaxel resulted in an approximately 50% reduction in thymidylate synthase activity (the molecular target of 5-fluorodeoxyuridine monophosphate, the active capecitabine anabolite) with an higher impact observed with DU145 cells than with PC3 cells. Neither erlotinib nor docetaxel alone displayed marked effects on thymidine phosphorylase activity (the enzyme that governs at the cellular level the final and crucial step in the activation cascade of capecitabine), in contrast to their combination that resulted in a strong increase in thymidine phosphorylase activity in PC3 cells. These data may serve as a rational basis for setting up clinical trials in advanced prostate cancer combining epidermal growth factor receptor-targeting agents like erlotinib together with docetaxel and capecitabine.
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PMID:Synergistic cytotoxic interaction in hormone-refractory prostate cancer with the triple combination docetaxel-erlotinib and 5-fluoro-5'-deoxyuridine. 1692 30


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