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)

We have prepared nine androgens substituted with fluorine at C-16 or C-20 to evaluate their potential, as positron emission tomographic (PET) imaging agents for prostatic cancer when labeled with the positron emitting radionuclide fluorine-18 (t1/2 = 110 min). These compounds represent members from the following classes of androgens: testosterone (T), 5 alpha-dihydrotestosterone (DHT), 7 alpha-methyl-19-nortestosterone (MNT), mibolerone (Mib), and metribolone (R1881). All of these compounds were prepared by functionalization of suitable androgen precursors, and the synthetic routes were developed to allow the introduction of fluorine by a fluoride ion displacement reaction late in the synthesis, as is required for the preparation of these compounds in fluorine-18 labeled form. We have also prepared four androgens in which the C-3 carbonyl or 17 beta-hydroxyl groups are replaced by fluorine. Most of the fluorine-substituted androgens show high affinity for the androgen receptor (AR), although fluorine substitution lowers their affinity by a small factor. None of the androgens where fluorine replaces oxygen functions at C-3 or C-17 have substantial affinity for AR. Derivatives of the natural androgens (T and DHT) as well as MNT have little affinity for other steroid hormone receptors (progesterone and mineralocorticoid receptors), whereas the Mib and R1881 derivatives have somewhat greater heterologous binding. With sex steroid binding protein, a human serum binding protein, the pattern of binding affinities is nearly the reverse, with derivatives of Mib, R1881 and MNT having low affinity, and DHT and T, high affinity. From these fluorine-substituted compounds, we can select several whose preparation in fluorine-18 labeled form for further tissue distribution studies is merited.
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PMID:Synthesis of high affinity fluorine-substituted ligands for the androgen receptor. Potential agents for imaging prostatic cancer by positron emission tomography. 159 61

The prevention of cancer by agents in our diet has led to the concept that oxygen radicals are a necessary component of a variety of human cancers including breast, colon and prostatic cancer. These cancers are putatively promoted by estradiol, bile acids and androgens. Epidemiological studies have shown that these cancers are suppressed in vegetarian populations. Vegetable components that may be responsible for this cancer prevention are Vitamin A, retinoids and protease inhibitors (PIs). These agents have been shown to suppress the formation of hydrogen peroxide in promoter-induced neutrophils. They also have been shown to block two-stage carcinogenesis and breast cancer when fed to animals. PIs also suppress experimentally-induced colon cancer and spontaneous liver cancer. Moreover, a new series of cancer-preventive agents, Sarcophytols (isolated by Fujiki and co-workers), are capable of suppressing two-stage carcinogenesis, breast and colon cancers in rodents when given in low concentrations. Sarcophytols were also active suppressors of H2O2 formation of 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced neutrophils. These observations point to an essential role of oxygen radicals in carcinogenesis. Suppression of the oxygen radical response of neutrophils in relation to cancer preventive agents is a facile assay of these important substances. The mechanism of action of oxygen radicals in promoting carcinogenesis is a multiple one, including: (1) activation of oncogenes, (2) modification of DNA bases, and (3) formation of single-strand breaks leading to poly(ADP)ribose polymerase activation.
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PMID:Prevention of cancer by agents that suppress oxygen radical formation. 206 Aug 47

Estramustine (EM), a complex between estradiol-17 beta and nornitrogen mustard, is commonly used in the treatment of prostatic cancer. The exact mechanism of action is unknown but has previously been considered to be mediated through non-DNA targets, specifically with the mitotic spindle, and to be related to the intact EM complex. In the present study, using different cell-systems (monocyte phagocytosis transformed fibroblasts, colon cancer cells), the EM cytotoxicity was also found to involve direct interaxtion with DNA and cell membranes. The interaction with DNA was shown by a DNA precipitation assay using 3H- and 14C- thymidine, and the cell membrane damage by using 86Rb- accumulation as a sensitive marker for active potassium uptake. EM effects in the fibroblasts were inhibited by various metal chelators and radical scavengers. Involvement of free oxygen radicals was further indicated in a cell-free system with an oxygen electrode. The EM inhibition of monocyte phagocytosis was related to the engulfment, and was not at all influenced by radical scavengers. In contrast to EM, neither of its components alone, or together, affected monocyte engulfment. Finally, it was shown that the colon cancer cell-line HT-29 was resistant to both of the two suggested and separate mechanisms for EM toxicity: an interaction with the microtubuli system by the intact EM complex and a more unspecific action mediated by free-oxygen radicals.
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PMID:The effect of estramustine on microtubuli is different from the direct action via oxygen radicals on DNA and cell membrane. 234 5

Lycopene is a carotenoid present in human blood (approximately 0.5 micromol/liter plasma), and the tissue levels vary from 1 nmol/g wet wt in adipose tissue to up to 20 nmol/g wet wt in adrenals and testes. Its biological activities include antioxidant activity (singlet oxygen quenching and peroxyl radical scavenging), induction of cell-cell communication, and growth control, but no provitamin A activity. Epidemiological studies suggest protective effects of lycopene on some types of cancer, e.g., prostate cancer. In vitro and in vivo studies on growth of tumor cells support this conclusion. The major sources of lycopene for the human are tomatoes and tomato products, and bioavailability from different food items varies considerably. Lycopene oxidation products have recently been identified in human serum. Suggested health effects of lycopene require further investigation.
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PMID:Lycopene: a biologically important carotenoid for humans? 895 Oct 28

The role of the retinoblastoma gene product, RB, in transmitting the signals of apoptosis is unclear, but RB is considered to be antiapoptotic because RB mediates cell cycle arrest that also can interrupt intracellular signaling pathways leading to apoptosis. Gamma-radiation can cause apoptosis, the process of programmed cell death, via several mechanisms including DNA damage, ceramide production, and the generation of free radical oxygen species. We investigated the effect of RB on radiation-induced apoptosis by restoring normal RB expression in DU-145 prostate cancer cells that have one deleted and one truncated RB gene. DU-145 cells are highly resistant to apoptosis induced either by radiation or by the addition of ceramide. Two independently derived RB-positive DU-145 derivative cell lines underwent apoptosis after irradiation or exposure to the cell permeable C2-ceramide. Apoptosis in the RB-positive cell lines was not associated with major changes in the cell cycle response to irradiation. RB-mediated apoptosis occurred in the absence of expression of caspases 8, 6, 3, and 7 and without detectable cleavage of poly(ADP)ribose polymerase. However, a specific inhibitor of serine proteases, Na-p-Tosyl-L-lysyl-chloromethyl ketone, inhibited radiation-induced apoptosis in DU-145 cells expressing RB. Radiation-induced apoptosis was preceded by an increase in JUN protein expression and accompanied by activation of the stress-related JUN kinase. Our data show that RB is proapoptotic in DU-145 cells and acts upstream of JUN expression and JNK activation.
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PMID:Radiation-induced apoptosis mediated by retinoblastoma protein. 969 55

A newly synthesized cyclic hydroxamic acid compound, BMD188 [cis-1-hydroxy-4-(1-naphthyl)-6-octylpiperidine-2-one], was found to induce the apoptotic death of cultured prostate cancer cells by activating caspase-3. Orally administered BMD188 significantly inhibited the primary growth of prostate cancer cells (Du145) orthotopically implanted into SCID mice. Mechanistic studies indicated that BMD188 did not alter the protein levels of several Bcl-2 family members. In contrast, the BMD188 effect required three essential factors: reactive oxygen species (ROS), the mitochondrial respiratory chain function, and proteases. First, the apoptosis-inducing effect of BMD188 could be blocked by ROS scavengers such as Desferal. Second, both BMD188-induced PARP cleavage as well as PC3 cell apoptosis could be dramatically inhibited by several complex-specific mitochondrial respiration blockers. The involvement of mitochondria was also supported by the observations that BMD188 dramatically altered the mitochondrial distribution and morphology without affecting the cellular ATP levels. Finally, the apoptosis-inducing effect of BMD188 in PC3 cells could be significantly inhibited by serine protease inhibitors (TPCK and TLCK) as well as by caspase inhibitors (zVAD-fmk and DEVD-CHO). Collectively, the present study suggests that BMD188 and its analogs may find clinical applications in the treatment of prostate cancer patients by inducing apoptotic death of prostate cancer cells.
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PMID:BMD188, A novel hydroxamic acid compound, demonstrates potent anti-prostate cancer effects in vitro and in vivo by inducing apoptosis: requirements for mitochondria, reactive oxygen species, and proteases. 976 36

Angiogenesis, the formation of new blood vessels from preexisting ones, is a fundamental stage in the metastatic pathway. For the primary tumor, this neovascularization provides nutrients and oxygen as well as a route by which metastatic tumor cells gain access to the circulatory system. Among these metastatic tumor cells, there are subgroups of cells that express an angiogenesis-inducing cells phenotype (AICs) as well as others that do not. Tumor cells not expressing the angiogenesis-inducing cells phenotype (non-AICs) invade new tissues and remain as dormant micrometastases unless they accompany AICs. Thus, either alone or with non-AICs, angiogenesis-inducing cells form rapidly growing, clinically detectable metastases. Much of the current research in this area is concentrated on the vascularization of primary tumors, but the regulation of angiogenesis by extravasating or invading tumor cells has not being extensively studied. We have developed a working model, which demonstrates that human metastatic prostate cancer cells (PC-3) appear to induce human vascular endothelial cells (HUVECs) to translocate across a Matrigel-coated 8 mm membrane. The parameters of this model (i.e. pore size, seeding-cell density, seeding times) were established using highly invasive murine melanoma cells (B16F10) seeded on murine microvascular endothelial cells (CD3). We have further modified our model in order to include a host compartment made of collagen gel, in order to mimic the in vivo site of metastases-induced angiogenesis.
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PMID:A novel in vitro system to study extravasated tumor cell-induced angiogenesis. 976 42

Physiologic or pathologically induced periods of exposure to relatively low levels of oxygen during pregnancy affect the expression and function of certain genes in the placenta. In this study, the differential display technique was utilized to identify genes that are regulated in cultured cytotrophoblast cells by exposure to low levels of oxygen. Using this approach, four genes, which have been designated HRF-1, HRF-2, HRF-6, and HRF-8, were cloned and partially characterized. Northern blot analysis showed that clones HRF-1 and HRF-2 were downregulated in response to exposure to low levels of oxygen, whereas expression of HRF-6 and HRF-8 was increased. DNA sequencing and sequence analysis revealed that HRF-1 may represent an alternatively spliced or tissue-specific form of the Kruppel family zinc finger protein znfp104 gene. Clone HRF-2 showed a high degree of identity with exons 9, 10 and 11 of N33, a gene that is located within a homozygously deleted region of metastatic prostate cancer. Clones HRF-6 and HRF-8 did not exhibit significant sequence identity with known sequences in GenBank and may represent novel genes. None of these genes have previously been shown to be present in trophoblast cells, nor have their expressions been shown to be regulated by oxygen. This study demonstrates that the differential display technique is a novel and effective method to analyse oxygen-mediated changes in gene expression in trophoblast cells.
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PMID:Differential display analysis of oxygen-mediated changes in gene expression in first trimester human trophoblast cells. 977 21

Studies have described the protective role of vitamin C (ascorbic acid) in certain types of cancer. In this study, we report the effects of vitamin C treatment of two androgen independent prostate cancer cell lines from human (PC3) and rat (Mat-Ly-Lu or MLL) sources. In vitro treatment of PC3 and MLL with sodium ascorbate acid (0-10 mM) resulted in a decrease in cell viability and thymidine incorporation into DNA. These effects of vit. C were dose and time dependent. Ascorbate induced these changes through the production of hydrogen peroxide since addition of catalase (100-300 units/ml), an enzyme that degrades hydrogen peroxide, inhibited the effects of ascorbate on these cell lines. In contrast, superoxide dismutase, an enzyme that dismutates superoxide and generates hydrogen peroxide did not prevent ascorbate-induced changes emphasizing the involvement of reactive oxygen species (ROS) in cellular damage. That singlet oxygen scavengers such as sodium azide and hydroquinone, hydroxyl radical scavengers such as D-mannitol and DL-alpha-tocopherol did not counteract the effects of ascorbate on thymidine incorporation suggests that these free radicals are not involved in cellular damage. In conclusion, these results suggest that vitamin C inhibits tumor growth by virtue of producing reactive oxygen species. These results suggest that ascorbate is a potent anticancer agent for prostate cancer cells.
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PMID:Effect of vitamin C on androgen independent prostate cancer cells (PC3 and Mat-Ly-Lu) in vitro: involvement of reactive oxygen species-effect on cell number, viability and DNA synthesis. 992 64

Glutathione-S-Transferases (GSTs) comprise a family of isoenzymes that provide protection to mammalian cells against electrophilic metabolites of carcinogens and reactive oxygen species. Previous studies have shown that the CpG-rich promoter region of the pi-class gene GSTP1 is methylated at single restriction sites in the majority of prostate cancers. In order to understand the nature of abnormal methylation of the GSTP1 gene in prostate cancer we undertook a detailed analysis of methylation at 131 CpG sites spanning the promoter and body of the gene. Our results show that DNA methylation is not confined to specific CpG sites in the promoter region of the GSTP1 gene but is extensive throughout the CpG island in prostate cancer cells. Furthermore we found that both alleles are abnormally methylated in this region. In normal prostate tissue, the entire CpG island was unmethylated, but extensive methylation was found outside the island in the body of the gene. Loss of GSTP1 expression correlated with DNA methylation of the CpG island in both prostate cancer cell lines and cancer tissues whereas methylation outside the CpG island in normal prostate tissue appeared to have no effect on gene expression.
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PMID:Detailed methylation analysis of the glutathione S-transferase pi (GSTP1) gene in prostate cancer. 1002 13


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