Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0376358 (prostate cancer)
59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Following intravenous administration to male rats, the uptake and retention by reproductive tissues of chromium-51, cobalt-57, iron-59, zinc-65 and tritium has been studied for up to 28 days. Chromium-51, 57Co, 59Fe and 3H were not or only transiently accumulated in gonads or accessory sex glands at concentrations greater than whole body concentrations. However, 65Zn was concentrated in the dorsolateral region of the prostate gland and autoradiography showed preferential uptake by epithelial cells and lumen of glands. When combined with other information available from the literature, this data would suggest that current models adequately describe the biokinetics of chromium, cobalt, iron and tritium in the prostate and testes and zinc in the testes. Uptake of zinc by the prostate would appear to be best described by an average value of 0.1% and a conservative value of 0.5%. Allowing for greater uptake of zinc (0.5%) by the prostate, after inhalation of 65Zn in a soluble form increases prostate dose by about 3 fold compared to current models. The pessimistic assumptions of a higher relative biological effectiveness (20) for all Auger emissions from 65Zn in cell nuclei and a heterogeneous distribution of 65Zn to sensitive cells in the prostate increases prostate dose by a further factor of 9. Even on the basis of these cautions estimates, occupational exposures to radioisotopes of these elements do not explain the excess of prostate cancer reported amongst some nuclear workers.
...
PMID:Biokinetics and dosimetry of chromium, cobalt, hydrogen, iron and zinc radionuclides in male reproductive tissues of the rat. 926 17

A new synthetic route to a variety of novel delta 16-17-azolyl steroids is described: it involves the nucleophilic vinylic "addition-elimination" substitution reaction of 3 beta-acetoxy-17-chloro-16-formylandrosta-5,16-diene (2) and azolyl nucleophiles. Some of these novel delta 16-17-azolyl steroids, 6, 17, 19, and 27-29, prepared in good overall yields, are very potent inhibitors of human and rat testicular P450(17) alpha. They are shown to be noncompetitive and appear to be slow-binding inhibitors of human P450(17) alpha. The most potent compounds are 3 beta-hydroxy-17-(1H-imidazol-1-yl)androsta-5,16-diene (17), 3 beta-hydroxy-17-(1H-1,2,3-triazol-1-yl)androsta-5,-16-diene (19), and 17-(1H-imidazol-1-yl)androsta-4,16-dien-3-one (28), with Ki values of 1.2, 1.4, and 1.9 nM, respectively, being 20-32 times more potent than ketoconazole (Ki = 38 nM). Spectroscopic studies with a modified form of human P450(17) alpha indicate that the inhibition process involves binding of steroidal azole nitrogen to the heme iron of the enzyme. Furthermore, some of these potent P450(17) alpha inhibitors (27-29) are also powerful inhibitors of steroid 5 alpha-reductase, and others (17 and 19) appear to exhibit strong antiandrogenic activity in cultures of the LNCaP human prostatic cancer cell line. These novel compounds with impressive dual biological activities make them strong candidates for development as therapeutic agents for treatment of prostate cancer and other disease states which depend on androgens.
...
PMID:Novel 17-azolyl steroids, potent inhibitors of human cytochrome 17 alpha-hydroxylase-C17,20-lyase (P450(17) alpha): potential agents for the treatment of prostate cancer. 952 64

This population-based, case-control study in King County, Washington examined supplement use in 697 incident prostate cancer cases (ages 40-64) identified from the Puget Sound Surveillance, Epidemiology and End Results program registry and 666 controls recruited from the same overall population using random-digit dialing sampling. Participants reported their frequency of use of three types of multivitamins and single supplements of vitamins A, C, and E, calcium, iron, and zinc over the 2 years before diagnosis. Logistic regression analyses controlled for age, race, education, family history of prostate cancer, body mass index, number of prostate-specific antigen tests in the previous 5 years, and dietary fat intake. Adjusted odds ratios (95% confidence limits) for the contrast of > or =7/week versus no use were as follows: multivitamins, 0.96 (0.73, 1.26); vitamin A, 0.59 (0.32, 1.06); vitamin C, 0.77 (0.57, 1.04); vitamin E, 0.76 (0.54, 1.08); calcium, 1.04 (0.61, 1.78); iron, 0.50 (0.13, 1.76); and zinc, 0.55 (0.30, 1.00). Odds ratios differed little when cases were stratified by stage of disease at diagnosis or by histopathological grade. There were significant dose-response effects for zinc and ordered dose-response trends for vitamins C and E. Overall, these results suggest that multivitamin use is not associated with prostate cancer risk, but use of individual supplements of zinc, vitamin C, and vitamin E may be protective. Further study is needed to investigate the direct role of these dietary supplements, as well as the role of lifestyle variables associated with supplement use, on prostate cancer risk.
...
PMID:Vitamin and mineral supplement use is associated with reduced risk of prostate cancer. 1054 17

17 alpha-Hydroxylase/C17-20-lyase (P450 17, CYP 17) and 5 alpha-reductase are the key enzymes in androgen biosynthesis and targets for the treatment of prostate cancer and benign prostatic hyperplasia. In the search of inhibitors for both enzymes, 23 pregnenolone- or progesterone-based steroids were synthesized bearing an oxime group connected directly or via a spacer to the steroidal D-ring. Tested for inhibition of human and rat P450 17, some pregnenolone (9, 11, 14) and a series of progesterone compounds (17-20) turned out to be highly active inhibitors of the human enzyme. The most active compound was Z-21-hydroxyiminopregna-5, 17(20)-dien-3 beta-ol (9) showing K(i) values of 44 and 3.4 nM for the human and rat enzymes, respectively, and a type II UV-difference spectrum indicating a coordinate bond between the oxime group and the heme iron. In contrast to the pregnenolones which showed no inhibition of 5 alpha-reductase isozymes 1 and 2, the progesterones 16, 17, 20, 21, and 23 showed marked inhibition, especially toward the type 2 enzyme. Compounds 17 and 20 were identified as potent dual inhibitors of both P450 17 and 5 alpha-reductase. Tested for selectivity, the most potent P450 17 inhibitors 9, 10, and 14 showed no or only marginal inhibition of P450 arom, P450 scc, and P450 TxA(2). Selected compounds were tested for inhibition of the target enzymes using whole-cell assays. Compounds 9-11 strongly inhibited P450 17 being coexpressed with NADPH-P450 reductase in E. coli cells, and 16, 20, and 23 markedly inhibited 5 alpha-reductase expressed in HEK 293 cells. Tested for in vivo activity, 9 (0.019 mmol/kg) decreased the plasma testosterone concentration in rats after 2 and 6 h by 57% and 44%.
...
PMID:Synthesis and evaluation of novel steroidal oxime inhibitors of P450 17 (17 alpha-hydroxylase/C17-20-lyase) and 5 alpha-reductase types 1 and 2. 1106 22

Recent and new results which support a drug-DNA covalent bonding mechanism for cell toxicity of the clinical antitumor drugs, daunorubicin, doxorubicin, and epidoxorubicin, are summarized. The mechanism involves the iron complex of the drugs inducing oxidative stress to yield formaldehyde, which then mediates covalent attachment to G-bases of DNA. At NGC sites the combination of covalent and non-covalent drug interactions serve to virtually crosslink the DNA. Structural data for virtual crosslinks are compared as a function of drug structure. Elucidation of the mechanism led to the synthesis and evaluation of drug formaldehyde conjugates, Daunoform, Doxoform, and Epidoxoform, as improved chemotherapeutics. Drug uptake, nuclear targeting, drug release, and cytotoxicity of the clinical drugs by sensitive and resistant breast and prostate cancer cells are contrasted with those of the corresponding formaldehyde conjugates. Conjugates are taken up better, retained longer, and are more toxic to a wide variety of tumor cells. The kinetics of drug release from Doxoform and Epidoxoform treated MCF-7/Adr cells are biexponential and correlate with the biexponential kinetics of drug release from extracellular DNA. The results of the lead conjugate, Epidoxoform, in the National Cancer Institute 60 human tumor cell screen are presented and discussed in terms of some resistance mechanisms. Epidoxoform shows increased toxicity to all panels relative to doxorubicin and epidoxorubicin, and this enhanced toxicity is especially evident with the more resistant cell lines.
...
PMID:Nuclear targeting and retention of anthracycline antitumor drugs in sensitive and resistant tumor cells. 1117 89

Insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) possesses both growth-inhibitory and -potentiating effects on cells that are independent of IGF action and are mediated through specific IGFBP-3 binding proteins/receptors located at the cell membrane, cytosol, or nuclear compartments and in the extracellular matrix. We have here characterized transferrin (Tf) as one of these IGFBP-3 binding proteins. Human serum was fractionated over an IGFBP-3 affinity column, and a 70-kDa protein was eluted, sequenced, and identified (through database searching and Western immunoblot) as human Tf. Tf bound IGFBP-3 but had negligible affinity to the other five IGFBPs, and iron-saturated holo-Tf bound IGFBP-3 more avidly than unsaturated Tf. Biosensor interaction analysis confirmed that this interaction is specific and sensitive, with a high association rate similar to IGF-I, and suggested that binding occurs in the vicinity of the IGFBP-3 nuclear localization site. As an independent confirmation of this interaction, using a yeast two-hybrid system, we cloned Tf from a human liver complementary DNA library as an IGFBP-3 protein partner. Tf treatment blocked IGFBP-3-induced cell proliferation in bladder smooth muscle cells, and IGFBP-3-induced apoptosis in prostate cancer cells. In summary, we have employed a combination of techniques to demonstrate that Tf specifically binds IGFBP-3, and we showed that this interaction has important physiological effects on cellular events.
...
PMID:Transferrin is an insulin-like growth factor-binding protein-3 binding protein. 1129 22

Experimental data show accumulation of superparamagnetic iron oxide (SPIO) particles in atherosclerotic plaques. SPIO uptake occurred in plaques, suggesting an increased endothelial permeability and macrophage infiltrates as signs of inflammatory plaque activity. We incidentally observed SPIO uptake in aortic and arterial wall segments in patients who had originally received the magnetic resonance (MR) contrast agent for staging lymph node metastases. Twenty patients (19 male, 1 female; mean age, 64; range, 41-78 years) with bladder or prostate cancer underwent MR imaging (MRI) using a T2*-weighted high-resolution gradient-echo sequence prior to and 24-36 hours after intravenous injection of 2.6 mg of Fe/kg of SPIO (Sinerem). The aorta, both common external and internal iliac, as well as both superficial femoral arteries, were retrospectively analyzed for atherosclerotic wall changes. One patient was excluded. A positive finding was defined as an area of pronounced signal loss on postcontrast images clearly confined to the arterial wall, which was absent in the precontrast examination or increased in size. Such a finding was observed in one to three arteries in 7 of the 19 patients. The pronounced signal loss in the wall of the aorta and pelvic arteries seen in part of an elderly patient population after intravenous SPIO administration strongly suggests that this contrast agent accumulates in human atherosclerotic plaques.
...
PMID:Magnetic resonance imaging of atherosclerotic plaques using superparamagnetic iron oxide particles. 1159 58

17 alpha-hydroxylase-C17, 20-lyase (P450 17, CYP 17) is a key enzyme in androgen biosynthesis and a target for the treatment of prostate cancer. In order to find novel inhibitors for this enzyme, several compounds bearing different moieties able to complex with the heme iron located in the active site of the enzyme were synthesized. The moieties were introduced into the 16-position of pregnenolone and progesterone. Their inhibitory activities toward human and rat CYP 17 were determined and compared to the activities of the corresponding 17-substituted compounds. It became apparent that the 16-substituted compounds were less active than the parent compounds: they were either moderate or poor inhibitors of the target enzyme. Tested for inhibition of human 5 alpha-reductase 1 and 2--a target for the treatment of benign prostatic hyperplasia (BPH)--the title compounds showed some inhibitory activity.
...
PMID:C16 and C17 substituted derivatives of pregnenolone and progesterone as inhibitors of 17alpha-hydroxylase-C17, 20-lyase: synthesis and biological evaluation. 1259 17

Estramustine phosphate (EMP) is a compound widely used for the treatment of hormone-refractory prostate cancer. In order to better understand the precise molecular mechanism(s) by which EMP exerts its effects on hormone-resistant PC3 prostate cancer cells, we have utilized microarray to interrogate 22,215 known genes to determine the gene expression profiles altered by EMP treatment. The purpose of this investigation was to identify gene expression profile first and then in future studies determine the specific role of these genes in EMP-induced apoptosis in prostate cancer cells. We found a total of 726 genes which showed >2 fold change after EMP treatment. Clustering analysis showed 12 different types of expression alteration. These genes were also subjected to cluster analysis according to their biological functions. We found that EMP regulated the expression of genes, which are critically involved in the regulation of cell growth, cell cycle, apoptosis, iron homeostasis, cytoskeleton and cell signaling transduction. Real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis was used to confirm the results of microarray, and the results of real-time quantitative RT-PCR were consistent with the microarray data. From these results, we conclude that EMP caused changes in the expression of a large number of genes that are related to the control of cell survival and physiological behaviors. The gene expression profiles may provide comprehensive molecular mechanism(s) by which EMP exerts its pleiotropic effects on prostate cancer cells. EMP-induced regulation of these genes may be further exploited for devising therapeutic strategies for prostate cancer.
...
PMID:Gene expression profiling reveals novel targets of estramustine phosphate in prostate cancer cells. 1515 21

Elevated body iron stores (serum ferritin >300 microg/L, transferrin saturation TS >50%) are associated with increased risk of liver and lung cancers. To determine whether such association also exists for prostate cancer (PC), we measured serum ferritin, serum iron, total iron-binding capacity (TIBC), and TS in serum samples from 34 men with newly diagnosed, untreated PC and 84 healthy men, ranging in age from 49-78 years. In contrast with other malignancies, men with PC had significantly lower mean concentrations of serum ferritin (156 microg/L) and TS (24.35%) than those without PC (ferritin, 245 microg/L; TS, 31.98%) (p<0.05). The 95% confidence intervals for ferritin were 109-203 microg/L and 205-286 microg/L, and those for TS were 20.29-28.4% and 28.35-35.61% for men with and without PC, respectively. Significant differences were observed between both groups in the distribution of serum ferritin (<100, 101-300, >300 microg/L) and TS (<16, 16-50, >50%) (p<0.05). A lower percentage of cases than of controls had serum ferritin (17.6% versus 29.8%) and TS (5.9% versus 14.7%) above normal. These differences persisted when the analysis was limited to African-American men (31 cases and 52 controls). Data suggest that elevated body iron stores are less common in men with PC compared to those without PC.
...
PMID:Serum ferritin levels and transferrin saturation in men with prostate cancer. 1516 Sep 79


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

---